SU-E-J-07: A Functional MR Protocol for the Pancreatic Tumor Delineation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andreychenko, A; Heerkens, H; Meijer, G

2014-06-01

Purpose: Pancreatic cancer is one of the cancers with the poorest survival prognosis. At the time of diagnosis most of pancreatic cancers are unresectable and those patients can be treated by radiotherapy. Radiotherapy for pancreatic cancer is limited due to uncertainties in CT-based delineations. MRI provides an excellent soft tissue contrast. Here, an MR protocol is developed to improve delineations for radiotherapy treatment of pancreatic cancer. In a later stage this protocol can also be used for on-line visualization of the pancreas during MRI guided treatments. Methods: Nine pancreatic cancer patients were included. The MR protocol included T2 weighted(T2w), T1more » weighted(T1w), diffusion weighted(DWI) and dynamic contrast enhanced(DCE) techniques. The tumor was delineated on T2w and T1w MRI by an experienced radiation oncologist. Healthy pancreas or pancreatitis (assigned by the oncologist based on T2w) areas were also delineated. Apparent diffusion coefficient(ADC), and area under the curve(AUC)/time to peak(TTP) maps were obtained from DWI and DCE scans, respectively. Results: A clear demarcation of tumor area was visible on b800 DWI images in 5 patients. ADC maps of those patients characterized tumor as an area with restricted water diffusion. Tumor delineations based on solely DCE were possible in 7 patients. In 6 of those patients AUC maps demonstrated tumor heterogeneity: a hypointense area with a hyperintense ring. TTP values clearly discriminated the tumor and the healthy pancreas but could not distinguish tumor and the pancreatitis accurately. Conclusion: MR imaging results in a more pronounced tumor contrast than contrast enhanced CT. The addition of quantitative, functional MRI provides valuable, additional information to the radiation oncologist on the spatial tumor extent by discriminating tumor from the healthy pancreas(TTP, DWI) and characterizing the tumor(ADC). Our findings indicate that tumor delineation in pancreatic cancer can

Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®)—Health Professional Version

Cancer.gov

Pancreatic neuroendocrine tumors (islet cell tumors) treatment includes surgery with curative intent and surgery for metastatic disease. Hormone therapy, chemotherapy and targeted therapy are sometimes used. Get detailed information on the treatment of this disease in this clinician summary.

Clinical applications of circulating tumor DNA and circulating tumor cells in pancreatic cancer.

PubMed

Riva, Francesca; Dronov, Oleksii I; Khomenko, Dmytro I; Huguet, Florence; Louvet, Christophe; Mariani, Pascale; Stern, Marc-Henri; Lantz, Olivier; Proudhon, Charlotte; Pierga, Jean-Yves; Bidard, Francois-Clement

2016-03-01

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type and is characterized by a dismal prognosis due to late diagnosis, local tumor invasion, frequent distant metastases and poor sensitivity to current therapy. In this context, circulating tumor cells and circulating tumor DNA constitute easily accessible blood-borne tumor biomarkers that may prove their clinical interest for screening, early diagnosis and metastatic risk assessment of PDAC. Moreover these markers represent a tool to assess PDAC mutational landscape. In this review, together with key biological findings, we summarize the clinical results obtained using "liquid biopsies" at the different stages of the disease, for early and metastatic diagnosis as well as monitoring during therapy. Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Endoscopic ultrasound-guided radiofrequency ablation for management of benign solid pancreatic tumors.

PubMed

Choi, Jun-Ho; Seo, Dong-Wan; Song, Tae Jun; Park, Do Hyun; Lee, Sang Soo; Lee, Sung Koo; Kim, Myung-Hwan

2018-05-04

 Radiofrequency ablation (RFA) has been increasingly employed in experimental and clinical settings for the management of pancreatic lesions. This study aimed to assess the safety and efficacy of endoscopic ultrasound (EUS)-guided RFA for benign solid pancreatic tumors.  In a single-center, prospective study, 10 patients with benign solid pancreatic tumors underwent EUS-RFA. After the RFA electrode had been inserted into the pancreatic mass, the radiofrequency generator was activated to deliver 50 W of ablation power.  Among the 10 patients, 16 sessions of EUS-RFA were successfully performed. Diagnoses included nonfunctioning neuroendocrine tumor (n = 7), solid pseudopapillary neoplasm (n = 2), and insulinoma (n = 1); the median largest diameter of the tumors was 20 mm (range 8 - 28 mm). During follow-up (median 13 months), radiologic complete response was achieved in seven patients. Two adverse events (12.4 %; 1 moderate and 1 mild) occurred.  EUS-RFA may be a safe and potentially effective treatment option in selected patients with benign solid pancreatic tumors. Multiple sessions may be required if there is a remnant tumor, and adverse events must be carefully monitored. © Georg Thieme Verlag KG Stuttgart · New York.

Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice.

PubMed

Jiang, Shu-Heng; Li, Jun; Dong, Fang-Yuan; Yang, Jian-Yu; Liu, De-Jun; Yang, Xiao-Mei; Wang, Ya-Hui; Yang, Min-Wei; Fu, Xue-Liang; Zhang, Xiao-Xin; Li, Qing; Pang, Xiu-Feng; Huo, Yan-Miao; Li, Jiao; Zhang, Jun-Feng; Lee, Ho-Young; Lee, Su-Jae; Qin, Wen-Xin; Gu, Jian-Ren; Sun, Yong-Wei; Zhang, Zhi-Gang

2017-07-01

Desmoplasia and poor vascularity cause severe metabolic stress in pancreatic ductal adenocarcinomas (PDACs). Serotonin (5-HT) is a neuromodulator with neurotransmitter and neuroendocrine functions that contributes to tumorigenesis. We investigated the role of 5-HT signaling in the growth of pancreatic tumors. We measured the levels of proteins that regulate 5-HT synthesis, packaging, and degradation in pancreata from Kras G12D/+ /Trp53 R172H/+ /Pdx1-Cre (KPC) mice, which develop pancreatic tumors, as well as in PDAC cell lines and a tissue microarray containing 81 human PDAC samples. We also analyzed expression levels of proteins involved in 5-HT synthesis and degradation by immunohistochemical analysis of a tissue microarray containing 311 PDAC specimens, and associated expression levels with patient survival times. 5-HT level in 14 matched PDAC tumor and non-tumor tissues were analyzed by ELISA. PDAC cell lines were incubated with 5-HT and cell survival and apoptosis were measured. We analyzed expression of the 5-HT receptor HTR2B in PDAC cells and effects of receptor agonists and antagonists, as well as HTR2B knockdown with small hairpin RNAs. We determined the effects of 5-HT stimulation on gene expression profiles of BxPC-3 cells. Regulation of glycolysis by 5-HT signaling via HTR2B was assessed by immunofluorescence and immunoprecipitation analyses, as well as by determination of the extracellular acid ratio, glucose consumption, and lactate production. Primary PDACs, with or without exposure to SB204741 (a selective antagonist of HTR2B), were grown as xenograft tumors in mice, and SB204741 was administered to tumor-bearing KPC mice; tumor growth and metabolism were measured by imaging analyses. In immunohistochemical analysis of a tissue microarray of PDAC specimens, increased levels of TPH1 and decreased level of MAOA, which regulate 5-HT synthesis and degradation, correlated with stage and size of PDACs and shorter patient survival time. We found levels

Is Diaphragm Motion a Good Surrogate for Liver Tumor Motion?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Juan; School of Information Science and Engineering, Shandong University, Jinan, Shandong; Cai, Jing

Purpose: To evaluate the relationship between liver tumor motion and diaphragm motion. Methods and Materials: Fourteen patients with hepatocellular carcinoma (10 of 14) or liver metastases (4 of 14) undergoing radiation therapy were included in this study. All patients underwent single-slice cine–magnetic resonance imaging simulations across the center of the tumor in 3 orthogonal planes. Tumor and diaphragm motion trajectories in the superior–inferior (SI), anterior–posterior (AP), and medial–lateral (ML) directions were obtained using an in-house-developed normalized cross-correlation–based tracking technique. Agreement between the tumor and diaphragm motion was assessed by calculating phase difference percentage, intraclass correlation coefficient, and Bland-Altman analysis (Diff).more » The distance between the tumor and tracked diaphragm area was analyzed to understand its impact on the correlation between the 2 motions. Results: Of all patients, the mean (±standard deviation) phase difference percentage values were 7.1% ± 1.1%, 4.5% ± 0.5%, and 17.5% ± 4.5% in the SI, AP, and ML directions, respectively. The mean intraclass correlation coefficient values were 0.98 ± 0.02, 0.97 ± 0.02, and 0.08 ± 0.06 in the SI, AP, and ML directions, respectively. The mean Diff values were 2.8 ± 1.4 mm, 2.4 ± 1.1 mm, and 2.2 ± 0.5 mm in the SI, AP, and ML directions, respectively. Tumor and diaphragm motions had high concordance when the distance between the tumor and tracked diaphragm area was small. Conclusions: This study showed that liver tumor motion had good correlation with diaphragm motion in the SI and AP directions, indicating diaphragm motion in the SI and AP directions could potentially be used as a reliable surrogate for liver tumor motion.« less

Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk.

PubMed

Orozco, Carlos A; Martinez-Bosch, Neus; Guerrero, Pedro E; Vinaixa, Judith; Dalotto-Moreno, Tomás; Iglesias, Mar; Moreno, Mireia; Djurec, Magdolna; Poirier, Françoise; Gabius, Hans-Joachim; Fernandez-Zapico, Martin E; Hwang, Rosa F; Guerra, Carmen; Rabinovich, Gabriel A; Navarro, Pilar

2018-04-17

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras -driven mouse model of PDA ( Ela-Kras G12V p53 -/- ) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.

Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer

PubMed Central

Paik, Woo Hyun; Ryu, Ji Kon; Jeong, Kyoung-Sin; Park, Jin Myung; Song, Byeong Jun; Lee, Sang Hyub; Kim, Yong-Tae; Yoon, Yong Bum

2014-01-01

AIM: To evaluate the anti-tumor effect of clobenpropit, which is a specific H3 antagonist and H4 agonist, in combination with gemcitabine in a pancreatic cancer cell line. METHODS: Three kinds of human pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and AsPC-1) were used in this study. Expression of H3 and H4 receptors in pancreatic cancer cells was identified with Western blotting. Effects of clobenpropit on cell proliferation, migration and apoptosis were evaluated. Alteration of epithelial and mesenchymal markers after administration of clobenpropit was analyzed. An in vivo study with a Panc-1 xenograft mouse model was also performed. RESULTS: H4 receptors were present as 2 subunits in human pancreatic cancer cells, while there was no expression of H3 receptor. Clobenpropit inhibited cell migration and increased apoptosis of pancreatic cancer cells in combination with gemcitabine. Clobenpropit up-regulated E-cadherin, but down-regulated vimentin and matrix metalloproteinase 9 in real-time polymerase chain reaction. Also, clobenpropit inhibited tumor growth (gemcitabine 294 ± 46 mg vs combination 154 ± 54 mg, P = 0.02) and enhanced apoptosis in combination with gemcitabine (control 2.5%, gemcitabine 25.8%, clobenpropit 9.7% and combination 40.9%, P = 0.001) by up-regulation of E-cadherin and down-regulation of Zeb1 in Panc-1 xenograft mouse. CONCLUSION: Clobenpropit enhanced the anti-tumor effect of gemcitabine in pancreatic cancer cells through inhibition of the epithelial-mesenchymal transition process. PMID:25024609

Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors.

PubMed

Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami; Ripoche, Doriane; Leteurtre, Emmanuelle; Chen, Yuan-Jia; Rehfeld, Jens F; Lepinasse, Florian; Hervieu, Valérie; Pattou, François; Vantyghem, Marie-Christine; Scoazec, Jean-Yves; Bertolino, Philippe; Zhang, Chang Xian

2015-10-01

The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a(+) and neurogenin 3-expressing (Ngn3(+)) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors

PubMed Central

Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami; Ripoche, Doriane; Leteurtre, Emmanuelle; Chen, Yuan-Jia; Rehfeld, Jens F.; Lepinasse, Florian; Hervieu, Valérie; Pattou, François; Vantyghem, Marie-Christine; Scoazec, Jean-Yves; Bertolino, Philippe

2015-01-01

The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a+ and neurogenin 3-expressing (Ngn3+) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors. PMID:26169832

Pancreatic neuroendocrine tumor with splenic vein tumor thrombus: A case report.

PubMed

Rodriguez, Rodrigo A; Overton, Heidi; Morris, Katherine T

2014-01-01

Pancreatic neuroendocrine tumors (PNET) are rare, often indolent malignancies. PNET are classified as functional or nonfunctional based on the secretion of hormones without a negative feedback loop; the latter account for up to 60% of PNET. Although PNET are associated with a better prognosis compared to pancreatic adenocarcinomas, they are often diagnosed in advanced stages, making them a significant source of morbidity for patients. Here we present a rare case of venous tumor thrombus arising from a nonfunctional PNET. A 44-year-old woman was referred for evaluation and treatment of a possible tail of pancreas PNET discovered during work-up for a 9 year history of intermittent subcostal pain. Previous endoscopic ultrasound with fine needle aspiration revealed a 3.5cm×3cm mass, with cytological diagnosis of neuroendocrine tumor. Patient was scheduled for laparoscopic distal pancreatectomy. During surgery the mass was found to encase the splenic vein leading the surgeon to perform an en bloc distal pancreatectomy and splenectomy. Pathologic analysis revealed a 1.8cm×5cm tumor thrombus lodged in the splenic vein. Nonfunctional PNET usually present in advanced stages and can be associated with venous tumor thrombi. Preoperative imaging may not accurately predict the presence of venous tumor thrombi. En bloc resection of primary tumor, involved organs and thrombus is the recommended treatment option and often results in long term survival. New multi-modality strategies are needed for detection of venous involvement in nonfunctional PNET to better assist with preoperative planning and counseling. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth.

PubMed

Shukla, Surendra K; Dasgupta, Aneesha; Mehla, Kamiya; Gunda, Venugopal; Vernucci, Enza; Souchek, Joshua; Goode, Gennifer; King, Ryan; Mishra, Anusha; Rai, Ibha; Nagarajan, Sangeetha; Chaika, Nina V; Yu, Fang; Singh, Pankaj K

2015-12-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models.

Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth

PubMed Central

Shukla, Surendra K.; Dasgupta, Aneesha; Mehla, Kamiya; Gunda, Venugopal; Vernucci, Enza; Souchek, Joshua; Goode, Gennifer; King, Ryan; Mishra, Anusha; Rai, Ibha; Nagarajan, Sangeetha; Chaika, Nina V.; Yu, Fang; Singh, Pankaj K.

2015-01-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models. PMID:26510913

Inhibition of the hedgehog pathway targets the tumor-associated stroma in pancreatic cancer.

PubMed

Hwang, Rosa F; Moore, Todd T; Hattersley, Maureen Mertens; Scarpitti, Meghan; Yang, Bin; Devereaux, Erik; Ramachandran, Vijaya; Arumugam, Thiruvengadam; Ji, Baoan; Logsdon, Craig D; Brown, Jeffrey L; Godin, Robert

2012-09-01

The Hedgehog (Hh) pathway has emerged as an important pathway in multiple tumor types and is thought to be dependent on a paracrine signaling mechanism. The purpose of this study was to determine the role of pancreatic cancer-associated fibroblasts (human pancreatic stellate cells, HPSCs) in Hh signaling. In addition, we evaluated the efficacy of a novel Hh antagonist, AZD8542, on tumor progression with an emphasis on the role of the stroma compartment. Expression of Hh pathway members and activation of the Hh pathway were analyzed in both HPSCs and pancreatic cancer cells. We tested the effects of Smoothened (SMO) inhibition with AZD8542 on tumor growth in vivo using an orthotopic model of pancreatic cancer containing varying amounts of stroma. HPSCs expressed high levels of SMO receptor and low levels of Hh ligands, whereas cancer cells showed the converse expression pattern. HPSC proliferation was stimulated by Sonic Hedgehog with upregulation of downstream GLI1 mRNA. These effects were abrogated by AZD8542 treatment. In an orthotopic model of pancreatic cancer, AZD8542 inhibited tumor growth only when HPSCs were present, implicating a paracrine signaling mechanism dependent on stroma. Further evidence of paracrine signaling of the Hh pathway in prostate and colon cancer models is provided, demonstrating the broader applicability of our findings. Based on the use of our novel human-derived pancreatic cancer stellate cells, our results suggest that Hh-targeted therapies primarily affect the tumor-associated stroma, rather than the epithelial compartment.

Preliminary results on the feasibility of using ultrasound to monitor intrafractional motion during radiation therapy for pancreatic cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Omari, Eenas A.; Erickson, Beth; Noid, George

Purpose: Substantial intrafraction organ motion during radiation therapy (RT) for pancreatic cancer is well recognized as a major limiting factor for accurate delivery of RT. The aim of this work is to determine the feasibility of monitoring the intrafractional motion of the pancreas or surrounding structures using ultrasound for RT delivery. Methods: Transabdominal ultrasound (TAUS) and 4DCT data were acquired on ten pancreatic cancer patients during radiation therapy process in a prospective study. In addition, TAUS and MRI were collected for five healthy volunteers. The portal vein (PV) and the head of the pancreas (HP) along with other structures weremore » contoured on these images. Volume changes, distance between the HP and PV, and motion difference between the HP and PV were measured to examine whether PV can be used as a motion surrogate for HP. TAUS images were acquired and processed using a research version of the Clarity autoscan ultrasound system (CAUS). Motion monitoring was performed with the ultrasound probe mounted on an arm fixed to the couch. Video segments of the monitoring sessions were captured. Results: On TAUS, PV is better visualized than HP. The measured mean volume deviation for all patients for the HP and PV was 1.4 and 0.6 ml, respectively. The distance between the HP and PV was close to a constant with 0.22 mm mean deviation throughout the ten breathing phases. The mean of the absolute motion difference for all patients was 1.7 ± 0.8 mm in LR, 1.5 ± 0.5 mm in AP, and 2.3 ± 0.7 mm in SI, suggesting that the PV is a good surrogate for HP motion estimation. By using this surrogate, the HP motion tracking using TAUS was demonstrated. Conclusions: Large intrafractional organ motion due to respiratory and/or bowel motion is a limiting factor in administering curative radiation doses to pancreatic tumors. The authors investigate the use of real-time ultrasound to track pancreas motion. Due to the poor visibility of the pancreas head on

Audiovisual biofeedback improves the correlation between internal/external surrogate motion and lung tumor motion.

PubMed

Lee, Danny; Greer, Peter B; Paganelli, Chiara; Ludbrook, Joanna Jane; Kim, Taeho; Keall, Paul

2018-03-01

Breathing management can reduce breath-to-breath (intrafraction) and day-by-day (interfraction) variability in breathing motion while utilizing the respiratory motion of internal and external surrogates for respiratory guidance. Audiovisual (AV) biofeedback, an interactive personalized breathing motion management system, has been developed to improve reproducibility of intra- and interfraction breathing motion. However, the assumption of the correlation of respiratory motion between surrogates and tumors is not always verified during medical imaging and radiation treatment. Therefore, the aim of the study was to test the hypothesis that the correlation of respiratory motion between surrogates and tumors is the same under free breathing without guidance (FB) and with AV biofeedback guidance for voluntary motion management. For 13 lung cancer patients receiving radiotherapy, 2D coronal and sagittal cine-MR images were acquired across two MRI sessions (pre- and mid-treatment) with two breathing conditions: (a) FB and (b) AV biofeedback, totaling 88 patient measurements. Simultaneously, the external respiratory motion of the abdomen was measured. The internal respiratory motion of the diaphragm and lung tumor was retrospectively measured from 2D coronal and sagittal cine-MR images. The correlation of respiratory motion between surrogates and tumors was calculated using Pearson's correlation coefficient for: (a) abdomen to tumor (abdomen-tumor) and (b) diaphragm to tumor (diaphragm-tumor). The correlations were compared between FB and AV biofeedback using several metrics: abdomen-tumor and diaphragm-tumor correlations with/without ≥5 mm tumor motion range and with/without adjusting for phase shifts between the signals. Compared to FB, AV biofeedback improved abdomen-tumor correlation by 11% (p = 0.12) from 0.53 to 0.59 and diaphragm-tumor correlation by 13% (p = 0.02) from 0.55 to 0.62. Compared to FB, AV biofeedback improved abdomen-tumor correlation by 17% (p = 0

microRNA-137 modulates pancreatic cancer cells tumor growth, invasion and sensitivity to chemotherapy

PubMed Central

Xiao, Jie; Peng, Feng; Yu, Chao; Wang, Min; Li, Xu; Li, Zhipeng; Jiang, Jianxin; Sun, Chengyi

2014-01-01

Background: We intended to investigate the role of microRNA 137 (miR-137) in regulating pancreatic cancer cells’ growth in vitro and tumor development in vivo. Methods: QTR-PCR was used to examine the expression of miR-137 in pancreatic cancer cell lines and tumor cells from human patients. Lentivirual vector containing miR-137 mimic was used to overexpress miR-137 in PANC-1 and MIA PaCa-2 cells. The effects of overexpressing miR-137 on pancreatic cancer cell invasion and chemo-sensitivity to 5-fluorouracil (5-FU) were examined by cell migration and survival essays in vitro. The molecular target of miR-137, pleiotropic growth factor (PTN), was down-regulated by siRNA to examine its effects on cancer cell invasion. MIA PaCa-2 cells with endogenously overexpressed miR-137 were transplanted into null mice to examine tumor growth in vivo. Results: We found miR-137 was markedly underexpressed in both pancreatic cancer cell lines and tumor cells from patients. In cancer cells, transfection of lentivirus containing miR-137 mimic was able to markedly upregulate endogenous expression of miR-137, inhibited cancer cell invasion and increased sensitivities to chemotherapy reagent 5-FU. PTN was significantly down-regulated by overexpressing miR-137 in pancreatic cancer cells, and knocking down PTN was effective to rescue the reduced cancer cell invasion ability caused by miR-137 overexpression. More importantly, overexpressing miR-137 led to significant inhibition on tumor formation, including reductions in tumor weight and tumor size in vivo. Conclusion: Our study demonstrated that miR-137 played an important role in pancreatic cancer development. It may become a new therapeutic target for gene therapy in patients suffered from pancreatic cancer. PMID:25550779

SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Soltani, M; Bazmara, H; Sefidgar, M

Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumorsmore » including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm{sup 3}, were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm{sup 3}, was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm{sup 3}, the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of

Pancreatic neuroendocrine tumor with splenic vein tumor thrombus: A case report

PubMed Central

Rodriguez, Rodrigo A.; Overton, Heidi; Morris, Katherine T.

2014-01-01

INTRODUCTION Pancreatic neuroendocrine tumors (PNET) are rare, often indolent malignancies. PNET are classified as functional or nonfunctional based on the secretion of hormones without a negative feedback loop; the latter account for up to 60% of PNET. Although PNET are associated with a better prognosis compared to pancreatic adenocarcinomas, they are often diagnosed in advanced stages, making them a significant source of morbidity for patients. Here we present a rare case of venous tumor thrombus arising from a nonfunctional PNET. PRESENTATION OF CASE A 44-year-old woman was referred for evaluation and treatment of a possible tail of pancreas PNET discovered during work-up for a 9 year history of intermittent subcostal pain. Previous endoscopic ultrasound with fine needle aspiration revealed a 3.5 cm × 3 cm mass, with cytological diagnosis of neuroendocrine tumor. Patient was scheduled for laparoscopic distal pancreatectomy. During surgery the mass was found to encase the splenic vein leading the surgeon to perform an en bloc distal pancreatectomy and splenectomy. Pathologic analysis revealed a 1.8 cm × 5 cm tumor thrombus lodged in the splenic vein. DISCUSSION Nonfunctional PNET usually present in advanced stages and can be associated with venous tumor thrombi. Preoperative imaging may not accurately predict the presence of venous tumor thrombi. CONCLUSION En bloc resection of primary tumor, involved organs and thrombus is the recommended treatment option and often results in long term survival. New multi-modality strategies are needed for detection of venous involvement in nonfunctional PNET to better assist with preoperative planning and counseling. PMID:25460491

uPAR-controlled oncolytic adenoviruses eliminate cancer stem cells in human pancreatic tumors.

PubMed

Sobrevals, Luciano; Mato-Berciano, Ana; Urtasun, Nerea; Mazo, Adela; Fillat, Cristina

2014-01-01

Pancreatic tumors contain cancer stem cells highly resistant to chemotherapy. The identification of therapies that can eliminate this population of cells might provide with more effective treatments. In the current work we evaluated the potential of oncolytic adenoviruses to act against pancreatic cancer stem cells (PCSC). PCSC from two patient-derived xenograft models were isolated from orthotopic pancreatic tumors treated with saline, or with the chemotherapeutic agent gemcitabine. An enrichment in the number of PCSC expressing the cell surface marker CD133 and a marked enhancement on tumorsphere formation was observed in gemcitabine treated tumors. No significant increase in the CD44, CD24, and epithelial-specific antigen (ESA) positive cells was observed. Neoplastic sphere-forming cells were susceptible to adenoviral infection and exposure to oncolytic adenoviruses resulted in elevated cytotoxicity with both Adwt and the tumor specific AduPARE1A adenovirus. In vivo, intravenous administration of a single dose of AduPARE1A in human-derived pancreatic xenografts led to a remarkable anti-tumor effect. In contrast to gemcitabine AduPARE1A treatment did not result in PCSC enrichment. No enrichment on tumorspheres neither on the CD133(+) population was detected. Therefore our data provide evidences of the relevance of uPAR-controlled oncolytic adenoviruses for the elimination of pancreatic cancer stem cells. © 2013.

[DIAGNOSIS OF VASCULAR INVASION BY PANCREATIC TUMORS].

PubMed

Dronov, O I; Zemskov, S V; Bakunets, P P

2016-02-01

Basing on analysis of own material (84 patients) and data of literature there was established, that vascular invasion by pancreatic tumors constitutes the main obstacle for conduction of the patients' radical treatment. Early diagnosis permits radical resectability of the patients, what constitutes the only one effective method of treatment. In vascular invasion by tumor a surgeon experience and professional preparation determines possibility of the extended operation performance with intervention on affected main vessel, enhancing the treatment radicalism.

Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.

PubMed

Sunamura, Makoto; Duda, Dan G; Ghattas, Maivel H; Lozonschi, Lucian; Motoi, Fuyuhiko; Yamauchi, Jun-Ichiro; Matsuno, Seiki; Shibahara, Shigeki; Abraham, Nader G

2003-01-01

Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease.

Determinants of surgical resection for pancreatic neuroendocrine tumors.

PubMed

Doi, Ryuichiro

2015-08-01

Pancreatic neuroendocrine tumors (pNETs) include functioning and non-functional tumors. Functioning tumors consist of tumors that produce a variety of hormones and their clinical effects. Therefore, determinants of resection of pNETs should be discussed for each group of tumors. Less than 10% of insulinomas are malignant, therefore more than 90% of the cases can be cured by surgical resection. Lymphadenectomy is generally not necessary in insulinoma operation. If preoperative localization of the insulinoma is completed, enucleation from the pancreatic body or tail, and distal pancreatectomy can be performed safely by laparoscopy. When preoperative localization of a sporadic insulinoma is not confirmed, surgical exploration is needed. Intraoperative localization of a tumor, intraoperative insulin sampling and frozen section are required. The crucial purpose of surgical resection is to control inappropriate insulin secretion by removing all insulinomas. Gastrinomas are usually located in the duodenum or pancreas, which secrete gastrin and cause Zollinger-Ellison syndrome (ZES). Duodenal gastrinomas are usually small, therefore they are not seen on preoperative imaging studies or endoscopic ultrasound, and can be found only at surgery if a duodenotomy is performed. In addition, lymph node metastasis is found in 40-60% of cases. Therefore, the experienced surgeons should direct operation for gastrinomas. Surgical exploration with duodenotomy should be performed at a laparotomy. Other functioning pNETs can occur in the pancreas or in other locations. Curative resection is always recommended whenever possible after optimal symptomatic control of the clinical syndrome by medical treatment. Indications for surgery depend on clinical symptom control, tumor size, location, extent, malignancy and presence of metastasis. A lot of non-functioning pNETs are found incidentally according to the quality improvement of imaging techniques. Localized, small, malignant non

Postoperative Outcomes of Enucleation and Standard Resections in Patients with a Pancreatic Neuroendocrine Tumor.

PubMed

Jilesen, Anneke P J; van Eijck, Casper H J; Busch, Olivier R C; van Gulik, Thomas M; Gouma, Dirk J; van Dijkum, Els J M Nieveen

2016-03-01

Either enucleation or more extended resection is performed to treat patients with pancreatic neuroendocrine tumor (pNET). Aim was to analyze the postoperative complications for each operation separately. Furthermore, independent risk factors for complications and incidence of pancreatic insufficiency were analyzed. Retrospective all resected patients from two academic hospitals in The Netherlands between 1992 and 2013 were included. Postoperative complications were scored by both ISGPS and Clavien-Dindo criteria. Based on tumor location, operations were compared. Independent risk factors for overall complications were identified. During long-term follow-up, pancreatic insufficiency and recurrent disease were analyzed. Tumor enucleation was performed in 60/205 patients (29%), pancreatoduodenectomy in 65/205 (31%), distal pancreatectomy in 72/205 (35%) and central pancreatectomy in 8/205 (4%) patients. Overall complications after tumor enucleation of the pancreatic head and pancreatoduodenectomy were comparable, 24/35 (69%) versus 52/65 (80%). The same was found after tumor enucleation and resection of the pancreatic tail (36 vs.58%). Number of re-interventions and readmissions were comparable between all operations. After pancreatoduodenectomy, 33/65 patients had lymph node metastasis and in patients with tumor size ≤2 cm, 55% had lymph node metastasis. Tumor in the head and BMI ≥25 kg/m(2) were independent risk factors for complications after enucleation. During follow-up, incidence of exocrine and endocrine insufficiency was significant higher after pancreatoduodenectomy (resp. 55 and 19%) compared to the tumor enucleation and distal pancreatectomy (resp. 5 and 7% vs. 8 and 13%). After tumor enucleation 19% developed recurrent disease. Since the complication rate, need for re-interventions and readmissions were comparable for all resections, tumor enucleation may be regarded as high risk. Appropriate operation should be based on tumor size, location, and

Saliva exosomes from pancreatic tumor-bearing mice modulate NK cell phenotype and antitumor cytotoxicity.

PubMed

Katsiougiannis, Stergios; Chia, David; Kim, Yong; Singh, Ram P; Wong, David T W

2017-03-01

Tumor exosomes are emerging as antitumor immunity regulators; however, their effects on secondary exosome secretion by distal organs have not been explored. We have previously demonstrated that suppression of exosomes at the distal tumor site of pancreatic ductal adenocarcinoma (PDAC) ablated the development of salivary biomarker profile. Here, we explore the function of salivary exosomes from tumor-bearing mice in immune surveillance. We provide evidence that salivary exosomes from mice with PDAC exhibit a suppressive effect that results in reduced tumor-killing capacity by NK cells. Salivary exosomes from mice with PDAC where pancreatic tumors were engineered to suppress exosome biogenesis failed to suppress NK cell cytotoxic potential against tumor cells, as opposed to salivary exosomes from mice with PDAC with normal tumor exosome biogenesis. These results reveal an important and previously unknown mechanism of antitumor immune regulation and provide new insights into our understanding of the alterations of this biofluid during tumor development.-Katsiougiannis, S., Chia, D., Kim, Y., Singh, R. P., Wong, D. T. W. Saliva exosomes from pancreatic tumor-bearing mice modulate NK cell phenotype and antitumor cytotoxicity. © FASEB.

State-of-the-art pancreatic MRI.

PubMed

Sandrasegaran, Kumaresan; Lin, Chen; Akisik, Fatih M; Tann, Mark

2010-07-01

The purpose of this article is to discuss the most current techniques used for pancreatic imaging, highlighting the advantages and disadvantages of state-of-the-art and emerging pulse sequences and their application to pancreatic disease. Given the technologic advances of the past decade, pancreatic MRI protocols have evolved. Most sequences can now be performed in one or a few breath-holds; 3D sequences with thin, contiguous slices offer improved spatial resolution; and better fat and motion suppression allow improved contrast resolution and image quality. The diagnostic potential of MRCP is now almost as good as ERCP, with pancreatic MRI as the main imaging technique to investigate biliopancreatic pain, chronic pancreatitis, and cystic pancreatic tumors at many institutions. In addition, functional information is provided with secretin-enhanced MRCP.

Somatostatin Receptor-1 Induces Cell Cycle Arrest and Inhibits Tumor Growth in Pancreatic Cancer

PubMed Central

Li, Min; Wang, Xiaochi; Li, Wei; Li, Fei; Yang, Hui; Wang, Hao; Brunicardi, F. Charles; Chen, Changyi; Yao, Qizhi; Fisher, William E.

2010-01-01

Functional somatostatin receptors (SSTRs) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G0/G1 growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n=5, p<0.05, t-test), and inhibited tumor weight by 69% and 47%, (n=5, p<0.05, t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer. PMID:18823376

Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

NASA Astrophysics Data System (ADS)

Koay, Eugene J.; Baio, Flavio E.; Ondari, Alexander; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya'an; Zhang, Joy; Court, Laurence; Bhosale, Priya R.; Tamm, Eric P.; Qayyum, Aliya; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffrey E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R.; Fleming, Jason B.

2014-12-01

There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

Duodenum-preserving resection and Roux-en-Y pancreatic jejunostomy in benign pancreatic head tumors.

PubMed

Yuan, Chun-Hui; Tao, Ming; Jia, Yi-Mu; Xiong, Jing-Wei; Zhang, Tong-Lin; Xiu, Dian-Rong

2014-11-28

This study was conducted to explore the feasibility of partial pancreatic head resection and Roux-en-Y pancreatic jejunostomy for the treatment of benign tumors of the pancreatic head (BTPH). From November 2006 to February 2009, four patients (three female and one male) with a mean age of 34.3 years (range: 21-48 years) underwent partial pancreatic head resection and Roux-en-Y pancreatic jejunostomy for the treatment of BTPH (diameters of 3.2-4.5 cm) using small incisions (5.1-7.2 cm). Preoperative symptoms include one case of repeated upper abdominal pain, one case of drowsiness and two cases with no obvious preoperative symptoms. All four surgeries were successfully performed. The mean operative time was 196.8 min (range 165-226 min), and average blood loss was 138.0 mL (range: 82-210 mL). The mean postoperative hospital stay was 7.5 d (range: 7-8 d). In one case, the main pancreatic duct was injured. Pathological examination confirmed that one patient suffered from mucinous cystadenoma, one exhibited insulinoma, and two patients had solid-pseudopapillary neoplasms. There were no deaths or complications observed during the perioperative period. All patients had no signs of recurrence of the BTPH within a follow-up period of 48-76 mo and had good quality of life without diabetes. Partial pancreatic head resection with Roux-en-Y pancreatic jejunostomy is feasible in selected patients with BTPH.

MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma.

PubMed

Tinder, Teresa L; Subramani, Durai B; Basu, Gargi D; Bradley, Judy M; Schettini, Jorge; Million, Arefayene; Skaar, Todd; Mukherjee, Pinku

2008-09-01

MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer.

MUC1 enhances tumor progression and contributes towards immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma

PubMed Central

Tinder, Teresa L.; Subramani, Durai B.; Basu, Gargi D.; Bradley, Judy M.; Schettini, Jorge; Million, Arefayene; Skaar, Todd

2008-01-01

MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune competent host. Significant enhancement in the development of pancreatic intraepithelial pre-neoplastic lesions (PanINs) and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and indoleamine 2,3, dioxygenase compared to PDA mice lacking MUC1, especially during early stages of tumor development. The increased pro-inflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease which in turn regulate the immune responses. Thus, the mouse model is ideally-suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

Pancreatic Neuroendocrine Tumor with Atypical Radiologic Presentation.

PubMed

Singh, Ramandeep; Calhoun, Sean; Shin, Minchul; Katz, Robert

2008-01-01

An atypical radiographic presentation of a rare non-functional pancreatic neuroendocrine tumor as seen on US, CT and MRI is described. Radiographic-pathologic correlation via gross autopsy specimens and immuno-histochemical staining demonstrates the pancreas to be markedly enlarged with extensive calcifications and numerous tiny cysts secondary to diffuse neoplastic infiltration without a focal mass.

Opportunities and Challenges for Pancreatic Circulating Tumor Cells.

PubMed

Nagrath, Sunitha; Jack, Rhonda M; Sahai, Vaibhav; Simeone, Diane M

2016-09-01

Sensitive and reproducible platforms have been developed for detection, isolation, and enrichment of circulating tumor cells (CTCs)-rare cells that enter the blood from solid tumors, including those of the breast, prostate gland, lung, pancreas, and colon. These might be used as biomarkers in diagnosis or determination of prognosis. CTCs are no longer simply detected and quantified; they are now used in ex vivo studies of anticancer agents and early detection. We review what we have recently learned about CTCs from pancreatic tumors, describing advances in their isolation and analysis and challenges to their clinical utility. We summarize technologies used to isolate CTCs from blood samples of patients with pancreatic cancer, including immunoaffinity and label-free physical attribute-based capture. We explain methods of CTC analysis and how findings from these studies might be used to detect cancer at earlier stages, monitor disease progression, and determine prognosis. We review studies that have expanded CTCs for testing of anticancer agents and how these approaches might be used to personalize treatment. Advances in the detection, isolation, and analysis of CTCs have increased our understanding of the dissemination and progression of pancreatic cancer. However, standardization of methodologies and prospective studies are needed for this emerging technology to have a significant effect on clinical care. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Extended pancreatectomy as defined by the ISGPS: useful in selected cases of pancreatic cancer but invaluable in other complex pancreatic tumors.

PubMed

Mitra, Abhishek; Pai, Esha; Dusane, Rohit; Ranganathan, Priya; DeSouza, Ashwin; Goel, Mahesh; Shrikhande, Shailesh V

2018-03-01

Extended pancreatectomy aimed at R0 resection of pancreatic tumors with adjacent vessel and organ involvement may be the only option for cure. This study was done with an objective to analyze the short- and long-term outcomes of extended pancreatic resections. All pancreatectomies performed between 2006 and 2015 were included. The pancreatectomies were classified as standard or extended, as per the International Study Group for Pancreatic Surgery. All surgical complications and terminologies were according to Clavien-Dindo classification and International Study Group for Pancreatic Surgery guidelines. Morbidity and mortality were primary outcomes and disease-free survival was a secondary outcome. Sixty-three extended and 620 standard pancreatectomies were performed. Major morbidity (Clavien grades III, IV and V) (37 vs. 29%, p = 0.21) and mortality (6 vs. 4%, p = 0.3) for extended pancreatectomies were comparable to those for standard pancreatectomies. Blood loss > 855 ml, need for blood transfusion, and tumor size were independent risk factors for morbidity, and the latter two for mortality. Standard pancreatectomies were associated with better 3-year disease-free survival than extended pancreatectomies (67 vs. 41%, p < 0.001). Extended pancreatectomies resulted in a significantly better median disease-free survival for non-pancreatic adenocarcinoma vs. pancreatic adenocarcinoma (33.3 vs. 9.5 months, p = 0.01). Extended pancreatectomies resulted in similar peri-operative morbidity and mortality compared to standard pancreatectomies. Although the survival of patients undergoing these complex procedures is inferior to standard pancreatectomies, they should be undertaken not only in selected cases of pancreatic cancer but even more so in other complex pancreatic tumors.

Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors

PubMed Central

Metz, David C.

2008-01-01

Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending upon whether the tumor is functional or not and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging and monitoring. Initially, therapy should be directed at the hormonal syndrome as this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas which are predominantly benign. Surgery is the only modality that offers the possibility of cure although it is generally noncurative in patients with Zollinger-Ellison syndrome or nonfunctional PETs with MEN1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection though debulking surgery is often felt to be useful in unresectable patients. Once metastatic, biotherapy is usually the first modality employed because it is generally well tolerated. Systemic or regional therapies are generally reserved until symptoms occur or tumor growth is rapid. Recently a number of newer agents, as well as receptor-directed radiotherapy, are being evalulated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization and management of PETs including discussion of peptide receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field. PMID:18703061

Clinical impact of circulating tumor cells and therapy response in pancreatic cancer.

PubMed

Okubo, K; Uenosono, Y; Arigami, T; Mataki, Y; Matsushita, D; Yanagita, S; Kurahara, H; Sakoda, M; Kijima, Y; Maemura, K; Natsugoe, S

2017-06-01

Among gastrointestinal cancers, the prognosis of pancreatic cancer is one of the poorest, with a large number of patients being diagnosed with unresectable tumors at the first visit to a doctor. The aims of the present study were to investigate the circulating tumor cells (CTC) in peripheral blood in order to assess their clinical significance in patients with pancreatic cancer. Sixty-five patients with advanced pancreatic cancer were enrolled. Borderline resectable pancreatic tumor patients were 9, and Unresectable patients were 56. The CellSearch system was used to isolate and enumerate CTCs. CTCs were identified in 21 out of 65 patients (32.3%) with only unresectable tumors. The overall survival rate was significantly lower in unresectable patients with than in those without CTCs (P = 0.0051). CTC positivity was significantly higher in patients with than in those without liver metastasis. A multivariate analysis identified the presence or absence of CTCs as an independent prognostic factor. Follow-up blood specimens were obtained from 40 patients treated with chemotherapy or chemoradiotherapy. The incidences of CTC positivity at three months after beginning of treatments in patients with progressive disease and stable disease or a partial response were 45.4% and 24.1%, respectively. The overall survival rate was significantly lower in patients with than in those without CTCs even after treatments (P = 0.045). CTC numbers represents a useful tool for predicting prognoses and therapeutic responses to chemotherapy among patients with advanced pancreatic cancer. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Carcinoma of the pancreatic head and periampullary region. Tumor staging with laparoscopy and laparoscopic ultrasonography.

PubMed Central

John, T G; Greig, J D; Carter, D C; Garden, O J

1995-01-01

OBJECTIVE: The authors performed a prospective evaluation of staging laparoscopy with laparoscopic ultrasonography in predicting surgical resectability in patients with carcinomas of the pancreatic head and periampullary region. SUMMARY BACKGROUND DATA: Pancreatic resection with curative intent is possible in a select minority of patients who have carcinomas of the pancreatic head and periampullary region. Patient selection is important to plan appropriate therapy and avoid unnecessary laparotomy in patients with unresectable disease. Laparoscopic ultrasonography is a novel technique that combines the proven benefits of staging laparoscopy with high resolution intraoperative ultrasound of the liver and pancreas, but which has yet to be evaluated critically in the staging of pancreatic malignancy. METHODS: A cohort of 40 consecutive patients referred to a tertiary referral center and with a diagnosis of potentially resectable pancreatic or periampullary cancer underwent staging laparoscopy with laparoscopic ultrasonography. The diagnostic accuracy of staging laparoscopy alone and in conjunction with laparoscopic ultrasonography was evaluated in predicting tumor resectability (absence of peritoneal or liver metastases; absence of malignant regional lymphadenopathy; tumor confined to pancreatic head or periampullary region). RESULTS: "Occult" metastatic lesions were demonstrated by staging laparoscopy in 14 patients (35%). Laparoscopic ultrasonography demonstrated factors confirming unresectable tumor in 23 patients (59%), provided staging information in addition to that of laparoscopy alone in 20 patients (53%), and changed the decision regarding tumor resectability in 10 patients (25%). Staging laparoscopy with laparoscopic ultrasonography was more specific and accurate in predicting tumor resectability than laparoscopy alone (88% and 89% versus 50% and 65%, respectively). CONCLUSIONS: Staging laparoscopy is indispensable in the detection of "occult" intra

Nonlocal Means Denoising of Self-Gated and k-Space Sorted 4-Dimensional Magnetic Resonance Imaging Using Block-Matching and 3-Dimensional Filtering: Implications for Pancreatic Tumor Registration and Segmentation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jin, Jun; McKenzie, Elizabeth; Fan, Zhaoyang

Purpose: To denoise self-gated k-space sorted 4-dimensional magnetic resonance imaging (SG-KS-4D-MRI) by applying a nonlocal means denoising filter, block-matching and 3-dimensional filtering (BM3D), to test its impact on the accuracy of 4D image deformable registration and automated tumor segmentation for pancreatic cancer patients. Methods and Materials: Nine patients with pancreatic cancer and abdominal SG-KS-4D-MRI were included in the study. Block-matching and 3D filtering was adapted to search in the axial slices/frames adjacent to the reference image patch in the spatial and temporal domains. The patches with high similarity to the reference patch were used to collectively denoise the 4D-MRI image. Themore » pancreas tumor was manually contoured on the first end-of-exhalation phase for both the raw and the denoised 4D-MRI. B-spline deformable registration was applied to the subsequent phases for contour propagation. The consistency of tumor volume defined by the standard deviation of gross tumor volumes from 10 breathing phases (σ-GTV), tumor motion trajectories in 3 cardinal motion planes, 4D-MRI imaging noise, and image contrast-to-noise ratio were compared between the raw and denoised groups. Results: Block-matching and 3D filtering visually and quantitatively reduced image noise by 52% and improved image contrast-to-noise ratio by 56%, without compromising soft tissue edge definitions. Automatic tumor segmentation is statistically more consistent on the denoised 4D-MRI (σ-GTV = 0.6 cm{sup 3}) than on the raw 4D-MRI (σ-GTV = 0.8 cm{sup 3}). Tumor end-of-exhalation location is also more reproducible on the denoised 4D-MRI than on the raw 4D-MRI in all 3 cardinal motion planes. Conclusions: Block-matching and 3D filtering can significantly reduce random image noise while maintaining structural features in the SG-KS-4D-MRI datasets. In this study of pancreatic tumor segmentation, automatic segmentation of GTV in the registered image sets is shown

Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors

PubMed Central

Krampitz, Geoffrey Wayne; George, Benson M.; Willingham, Stephen B.; Volkmer, Jens-Peter; Weiskopf, Kipp; Jahchan, Nadine; Newman, Aaron M.; Sahoo, Debashis; Zemek, Allison J.; Yanovsky, Rebecca L.; Nguyen, Julia K.; Schnorr, Peter J.; Mazur, Pawel K.; Sage, Julien; Longacre, Teri A.; Visser, Brendan C.; Poultsides, George A.; Norton, Jeffrey A.; Weissman, Irving L.

2016-01-01

Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with limited therapeutic options. Consequently, most patients with advanced disease die from tumor progression. Current evidence indicates that a subset of cancer cells is responsible for tumor development, metastasis, and recurrence, and targeting these tumor-initiating cells is necessary to eradicate tumors. However, tumor-initiating cells and the biological processes that promote pathogenesis remain largely uncharacterized in PanNETs. Here we profile primary and metastatic tumors from an index patient and demonstrate that MET proto-oncogene activation is important for tumor growth in PanNET xenograft models. We identify a highly tumorigenic cell population within several independent surgically acquired PanNETs characterized by increased cell-surface protein CD90 expression and aldehyde dehydrogenase A1 (ALDHA1) activity, and provide in vitro and in vivo evidence for their stem-like properties. We performed proteomic profiling of 332 antigens in two cell lines and four primary tumors, and showed that CD47, a cell-surface protein that acts as a “don’t eat me” signal co-opted by cancers to evade innate immune surveillance, is ubiquitously expressed. Moreover, CD47 coexpresses with MET and is enriched in CD90hi cells. Furthermore, blocking CD47 signaling promotes engulfment of tumor cells by macrophages in vitro and inhibits xenograft tumor growth, prevents metastases, and prolongs survival in vivo. PMID:27035983

CD133+ tumor initiating cells in a syngenic murine model of pancreatic cancer respond to Minnelide.

PubMed

Banerjee, Sulagna; Nomura, Alice; Sangwan, Veena; Chugh, Rohit; Dudeja, Vikas; Vickers, Selwyn M; Saluja, Ashok

2014-05-01

Pancreatic adenocarcinoma is the fourth leading cause for cancer-related mortality with a survival rate of less than 5%. Late diagnosis and lack of effective chemotherapeutic regimen contribute to these grim survival statistics. Relapse of any tumor is largely attributed to the presence of tumor-initiating cells (TIC) or cancer stem cells (CSC). These cells are considered as hurdles to cancer therapy as no known chemotherapeutic compound is reported to target them. Thus, there is an urgent need to develop a TIC-targeted therapy for pancreatic cancer. We isolated CD133(+) cells from a spontaneous pancreatic ductal adenocarcinoma mouse model and studied both surface expression, molecular markers of pancreatic TICs. We also studied tumor initiation properties by implanting low numbers of CD133(+) cells in immune competent mice. Effect of Minnelide, a drug currently under phase I clinical trial, was studied on the tumors derived from the CD133(+) cells. Our study showed for the first time that CD133(+) population demonstrated all the molecular markers for pancreatic TIC. These cells initiated tumors in immunocompetent mouse models and showed increased expression of prosurvival and proinvasive proteins compared to the CD133(-) non-TIC population. Our study further showed that Minnelide was very efficient in downregulating both CD133(-) and CD133(+) population in the tumors, resulting in a 60% decrease in tumor volume compared with the untreated ones. As Minnelide is currently under phase I clinical trial, its evaluation in reducing tumor burden by decreasing TIC as well as non-TIC population suggests its potential as an effective therapy. ©2014 AACR.

Intraductal delivery of adenoviruses targets pancreatic tumors in transgenic Ela-myc mice and orthotopic xenografts.

PubMed

José, Anabel; Sobrevals, Luciano; Miguel Camacho-Sánchez, Juan; Huch, Meritxell; Andreu, Núria; Ayuso, Eduard; Navarro, Pilar; Alemany, Ramon; Fillat, Cristina

2013-01-01

Gene-based anticancer therapies delivered by adenoviruses are limited by the poor viral distribution into the tumor. In the current work we have explored the feasibility of targeting pancreatic tumors through a loco-regional route. We have taken advantage of the ductal network in the pancreas to retrogradelly inject adenoviruses through the common bile duct in two different mouse models of pancreatic carcinogenesis: The transgenic Ela-myc mice that develop mixed neoplasms displaying both acinar-like and duct-like neoplastic cells affecting the whole pancreas; and mice bearing PANC-1 and BxPC-3 orthotopic xenografts that constitute a model of localized human neoplastic tumors. We studied tumor targeting and the anticancer effects of newly thymidine kinase-engineered adenoviruses both in vitro and in vivo, and conducted comparative studies between intraductal or intravenous administration. Our data indicate that the intraductal delivery of adenovirus efficiently targets pancreatic tumors in the two mouse models. The in vivo application of AduPARTKT plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TKT oncolytic adenoviruses significantly improved mean survival of mice bearing PANC-1 and BxPC-3 pancreatic xenografts from 30 to 52 days and from 20 to 68 days respectively (p less than 0.0001) when combined with GCV. Of notice, both AduPARTKT and ICOVIR15-TKT antitumoral responses were stronger by ductal viral application than intravenously, in line with the 38-fold increase in pancreas transduction observed upon ductal administration. In summary our data show that cytotoxic adenoviruses retrogradelly injected to the pancreas can be a feasible approach to treat localized pancreatic tumors.

WE-G-18C-06: Is Diaphragm Motion a Good Surrogate for Liver Tumor Motion?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, J; School of Information Science and Engineering, Shandong University, Jinan, Shandong; Cai, J

2014-06-15

Purpose: To investigate whether diaphragm motion is a good surrogate for liver tumor motion by comparing their motion trajectories obtained from cine-MRI. Methods: Fourteen patients with hepatocellular carcinoma (10/14) or liver metastases (4/14) undergoing radiation therapy were included in this study. All patients underwent single-slice 2D cine-MRI simulations across the center of the tumor in three orthogonal planes. Tumor and diaphragm motion trajectories in the superior-inferior (SI), anteriorposterior (AP), and medial-lateral (ML) directions were obtained using the normalized cross-correlation based tracking technique. Agreement between tumor and diaphragm motions was assessed by calculating the phase difference percentage (PDP), intra-class correlation coefficientmore » (ICC), Bland-Altman analysis (Diffs) and paired t-test. The distance (D) between tumor and tracked diaphragm area was analyzed to understand its impact on the correlation between tumor and diaphragm motions. Results: Of all patients, the means (±standard deviations) of PDP were 7.1 (±1.1)%, 4.5 (±0.5)% and 17.5 (±4.5)% in the SI, AP and ML directions, respectively. The means of ICC were 0.98 (±0.02), 0.97 (±0.02), and 0.08 (±0.06) in the SI, AP and ML directions, respectively. The Diffs were 2.8 (±1.4) mm, 2.4 (±1.1) mm, and 2.2 (±0.5) mm in the SI, AP and ML directions, respectively. The p-values derived from the paired t-test were < 0.02 in SI and AP directions, whereas were > 0.58 in ML direction primarily due to the small motion in ML direction. Tumor and diaphragmatic motion had high concordance when the distance between the tumor and tracked diaphragm areas was small. Conclusion: Preliminary results showed that liver tumor motion had good correlations with diaphragm motion in the SI and AP directions, indicating diaphragm motion in the SI and AP directions could potentially be a reliable surrogate for liver tumor motion. NIH (1R21CA165384-01A1), Golfers Against Cancer (GAC

99mTc-HYNIC-TOC imaging in the evaluation of pancreatic masses which are potential neuroendocrine tumors.

PubMed

Qiao, Zhen; Zhang, Jingjing; Jin, Xiaona; Huo, Li; Zhu, Zhaohui; Xing, Haiqun; Li, Fang

2015-05-01

The aim of this investigation was to determine the accuracy of the findings and the diagnoses of Tc-hydrazinonicotinyl-Tyr3-octreotide scan (Tc-HYNIC-TOC imaging) in patients with pancreatic masses which were potential neuroendocrine tumors. Records of total 20 patients with pancreatic masses were retrospectively reviewed. All of the patients had been revealed by abdominal contrast CT and possibility of neuroendocrine tumors could not be excluded by CT imaging before Tc-HYNIC-TOC imaging. Tc-HYNIC-TOC imaging was performed at 1 and 4 hours post-tracer injection, and SPECT/CT images of the abdomen were also acquired. The image findings were compared to final diagnoses which were made from pathological examination. Among all 20 pancreatic masses evaluated, there were 16 malignant lesions which included 1 ductal adenocarcinoma and 15 neuroendocrine tumors. Tc-HYNIC-TOC imaging identified 14 of 15 pancreatic neuroendocrine tumors and excluded 4 of 5 lesions which were not neuroendocrine tumors. The overall sensitivity, specificity, and accuracy was therefore 93.3% (14 of 15), 80% (4 of 5), and 90.0% (18 of 20), respectively, in our patient population. Tc-HYNIC-TOC imaging provides reasonable accuracy in the evaluation pancreatic mass suspected to be neuroendocrine tumors.

Diabetic Ketoacidosis with Concurrent Pancreatitis, Pancreatic β Islet Cell Tumor, and Adrenal Disease in an Obese Ferret (Mustela putorius furo)

PubMed Central

Phair, Kristen A; Carpenter, James W; Schermerhorn, Thomas; Ganta, Chanran K; DeBey, Brad M

2011-01-01

A 5.5-y-old spayed female ferret (Mustela putorius furo) with a history of adrenal disease, respiratory disease, and chronic obesity was evaluated for progressive lethargy and ataxia, diminished appetite, and possible polyuria and polydipsia. Physical examination revealed obesity, lethargy, tachypnea, dyspnea, a pendulous abdomen, significant weakness and ataxia of the hindlimbs, prolonged skin tenting, and mild tail-tip alopecia. Clinicopathologic analysis revealed severe hyperglycemia, azotemia, an increased anion gap, glucosuria, ketonuria, proteinuria, and hematuria. Abdominal ultrasonography showed hyperechoic hepatomegaly, bilateral adrenomegaly, splenic nodules, mild peritoneal effusion, and thickened and mildly hypoechoic limbs of the pancreas with surrounding hyperechoic mesentery. Fine-needle aspirates of the liver were highly suggestive of hepatic lipidosis. In light of a diagnosis of concurrent diabetic ketoacidosis and pancreatitis, the ferret was treated with fluid therapy, regular and long-acting insulin administration, and pain medication. However, electrolyte derangements, metabolic acidosis, dyspnea, and the clinical appearance of the ferret progressively worsened despite treatment, and euthanasia was elected. Necropsy revealed severe hepatic lipidosis, severe suppurative pancreatitis and vacuolar degeneration of pancreatic islet cells, a pancreatic β islet cell tumor, bilateral adrenal cortical adenomas, and myocardial fibrosis. To our knowledge, this case represents the first report of concurrent diabetes mellitus, pancreatitis, pancreatic β islet cell tumor (insulinoma), and adrenal disease in a domestic ferret. The simultaneous existence of 3 endocrine diseases, pancreatitis, and their associated complications is a unique and clinically challenging situation. PMID:21838985

15-Lipoxygenase-1 Production is Lost in Pancreatic Cancer and Overexpression of the Gene Inhibits Tumor Cell Growth1

PubMed Central

Hennig, René; Kehl, Timo; Noor, Seema; Ding, Xian-Zhong; Rao, Sambasiva M; Bergmann, Frank; Fürstenberger, Gerhard; Büchler, Markus W; Friess, Helmut; Krieg, Peter; Adrian, Thomas E

2007-01-01

Pancreatic cancer patients have an abysmal prognosis because of late diagnosis and lack of therapeutic options. Pancreatic intraepithelial neoplasias (PanINs), the precursor lesions, are a potential target for chemoprevention. Targeting eicosanoid pathways is an obvious choice because 5-lipoxygenase (5-LOX) has been suggested as a tumor promoter in pancreatic carcinogenesis. Here we provide evidence that 15-lipoxygenase-1 (15-LOX-1) expression and activity may exert antitumorigenic effects in pancreatic cancer. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis showed absence or very weak expression of 15-LOX-1 in all pancreatic cancer cell lines tested. 15-LOX-1 was strongly stained in normal ductal cells, tubular complexes, and centroacinar cells, but no staining was seen in islets, cancer cells, PanIN lesions, or in tumor cells in lymph node metastases, indicating that 15-LOX-1 expression is lost during tumor development in human pancreas. Overexpression of 15-LOX-1 in pancreatic tumor cells or treatment with its arachidonic acid-derived metabolite resulted in decreased cell growth. These findings provide evidence that loss of 15-LOX-1 may play an important role in pancreatic carcinogenesis, possibly as a tumor suppressor gene. Thus, induction of 15-LOX-1 expression may be an attractive option for the prevention and treatment of pancreatic cancer. PMID:18030360

Systematic review on the role of serum tumor markers in the detection of recurrent pancreatic cancer.

PubMed

Daamen, Lois A; Groot, Vincent P; Heerkens, Hanne D; Intven, Martijn P W; van Santvoort, Hjalmar C; Molenaar, I Quintus

2018-04-01

Biomarker testing can be helpful to monitor disease progression after resection of pancreatic cancer. This systematic review aims to give an overview of the literature on the diagnostic value of serum tumor markers for the detection of recurrent pancreatic cancer during follow-up. A systematic search was performed to 2 October 2017. All studies reporting on the diagnostic value of postoperatively measured serum biomarkers for the detection of pancreatic cancer recurrence were included. Data on diagnostic accuracy of tumor markers were extracted. Forest plots and pooled values of sensitivity and specificity were calculated. Four articles described test results of CA 19-9. A pooled sensitivity and specificity of respectively 0.73 (95% CI 0.66-0.80) and 0.83 (95% CI 0.73-0.91) were calculated. One article reported on CEA, showing a sensitivity of 50% and specificity of 65%. No other serum tumor markers were discussed for surveillance purposes in the current literature. Although testing of serum CA 19-9 has considerable limitations, CA 19-9 remains the most used serum tumor marker for surveillance after surgical resection of pancreatic cancer. Further studies are needed to assess the role of serum tumor marker testing in the detection of recurrent pancreatic cancer and to optimize surveillance strategies. Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Acoustic radiation force impulse shear wave elastography (ARFI) of acute and chronic pancreatitis and pancreatic tumor.

PubMed

Goertz, Ruediger S; Schuderer, Johanna; Strobel, Deike; Pfeifer, Lukas; Neurath, Markus F; Wildner, Dane

2016-12-01

Acoustic Radiation Force Impulse (ARFI) elastography evaluates tissue stiffness non-invasively and has rarely been applied to pancreas examinations so far. In a prospective and retrospective analysis, ARFI shear wave velocities of healthy parenchyma, pancreatic lipomatosis, acute and chronic pancreatitis, adenocarcinoma and neuroendocrine tumor (NET) of the pancreas were evaluated and compared. In 95 patients ARFI elastography of the pancreatic head, and also of the tail for a specific group, was analysed retrospectively. Additionally, prospectively in 100 patients ARFI was performed in the head and tail of the pancreas. A total of 195 patients were included in the study. Healthy parenchyma (n=21) and lipomatosis (n=30) showed similar shear wave velocities of about 1.3m/s. Acute pancreatitis (n=35), chronic pancreatitis (n=53) and adenocarcinoma (n=52) showed consecutively increasing ARFI values, respectively. NET (n=4) revealed the highest shear wave velocities amounting to 3.62m/s. ARFI elastography showed relevant differences between acute pancreatitis and chronic pancreatitis or adenocarcinoma. With a cut-off value of 1.74m/s for the diagnosis of a malignant disease the sensitivity was 91.1% whereas the specificity amounted to 60.4%. ARFI shear wave velocities present differences in various pathologies of the pancreas. Acute and chronic pancreatitis as well as neoplastic lesions show high ARFI values. Very high elasticity values may indicate malignant disease of the pancreas. However, there is a considerable overlap between the entities. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Targeted Therapies Improve Survival for Patients with Pancreatic Neuroendocrine Tumors

Cancer.gov

In 2011, based on initial findings from two clinical trials, the Food and Drug Administration approved sunitinib and everolimus for patients with pancreatic neuroendocrine tumors. Updated results from the everolimus trial were published in September 2016.

Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling

PubMed Central

Tan, Xiang-Lin; Bhattacharyya, Kalyan K.; Dutta, Shamit K.; Bamlet, William R.; Rabe, Kari G.; Wang, Enfeng; Smyrk, Thomas C.; Oberg, Ann L.; Petersen, Gloria M.; Mukhopadhyay, Debabrata

2015-01-01

Objectives To further elucidate anti-cancer mechanisms of metformin again pancreatic cancer, we evaluated inhibitory effects of metformin on pancreatic tumorigenesis in a genetically-engineered mouse model, and investigated its possible anti-inflammatory and anti-angiogenesis effects. Methods Six-week old LSL-KrasG12D/+;Trp53F2-10 mice (10 per group) were administered once daily intraperitoneally with saline (control) for one week or metformin (125 mg/kg) for one week (Met_1wk) or three weeks (Met_3wk) prior to tumor initiation. All mice continued with their respective injections for six weeks post-tumor initiation. Molecular changes were evaluated by quantitative polymerase chain reaction (PCR), immunohistochemistry, and Western blotting. Results At euthanasia, pancreatic tumor volume in Met_1wk (median, 181.8 mm3) and Met_3wk (median, 137.9 mm3) groups was significantly lower than the control group (median, 481.1 mm3) (P = 0.001 and 0.0009, respectively). No significant difference was observed between Met_1wk and Met_3wk groups (P = 0.51). These results were further confirmed using tumor weight and tumor burden measurements. Furthermore, metformin treatment decreased the phosphorylation of nuclear factor κB (NFκB) and signal transducer and activator of transcription 3 (STAT3) as well as the expression of Sp1 transcription factor and several NFκB-regulated genes. Conclusions Metformin may inhibit pancreatic tumorigenesis by modulating multiple molecular targets in inflammatory pathways. PMID:25875801

Genetic analysis of circulating tumor cells in pancreatic cancer patients: A pilot study.

PubMed

Görner, Karin; Bachmann, Jeannine; Holzhauer, Claudia; Kirchner, Roland; Raba, Katharina; Fischer, Johannes C; Martignoni, Marc E; Schiemann, Matthias; Alunni-Fabbroni, Marianna

2015-07-01

Pancreatic cancer is one of the most aggressive malignant tumors, mainly due to an aggressive metastasis spreading. In recent years, circulating tumor cells became associated to tumor metastasis. Little is known about their expression profiles. The aim of this study was to develop a complete workflow making it possible to isolate circulating tumor cells from patients with pancreatic cancer and their genetic characterization. We show that the proposed workflow offers a technical sensitivity and specificity high enough to detect and isolate single tumor cells. Moreover our approach makes feasible to genetically characterize single CTCs. Our work discloses a complete workflow to detect, count and genetically analyze individual CTCs isolated from blood samples. This method has a central impact on the early detection of metastasis development. The combination of cell quantification and genetic analysis provides the clinicians with a powerful tool not available so far. Copyright © 2015. Published by Elsevier Inc.

A Mouse to Human Search for Plasma Proteome Changes Associated with Pancreatic Tumor Development

PubMed Central

Faca, Vitor M; Song, Kenneth S; Wang, Hong; Zhang, Qing; Krasnoselsky, Alexei L; Newcomb, Lisa F; Plentz, Ruben R; Gurumurthy, Sushma; Redston, Mark S; Pitteri, Sharon J; Pereira-Faca, Sandra R; Ireton, Renee C; Katayama, Hiroyuki; Glukhova, Veronika; Phanstiel, Douglas; Brenner, Dean E; Anderson, Michelle A; Misek, David; Scholler, Nathalie; Urban, Nicole D; Barnett, Matt J; Edelstein, Cim; Goodman, Gary E; Thornquist, Mark D; McIntosh, Martin W; DePinho, Ronald A; Bardeesy, Nabeel; Hanash, Samir M

2008-01-01

Background The complexity and heterogeneity of the human plasma proteome have presented significant challenges in the identification of protein changes associated with tumor development. Refined genetically engineered mouse (GEM) models of human cancer have been shown to faithfully recapitulate the molecular, biological, and clinical features of human disease. Here, we sought to exploit the merits of a well-characterized GEM model of pancreatic cancer to determine whether proteomics technologies allow identification of protein changes associated with tumor development and whether such changes are relevant to human pancreatic cancer. Methods and Findings Plasma was sampled from mice at early and advanced stages of tumor development and from matched controls. Using a proteomic approach based on extensive protein fractionation, we confidently identified 1,442 proteins that were distributed across seven orders of magnitude of abundance in plasma. Analysis of proteins chosen on the basis of increased levels in plasma from tumor-bearing mice and corroborating protein or RNA expression in tissue documented concordance in the blood from 30 newly diagnosed patients with pancreatic cancer relative to 30 control specimens. A panel of five proteins selected on the basis of their increased level at an early stage of tumor development in the mouse was tested in a blinded study in 26 humans from the CARET (Carotene and Retinol Efficacy Trial) cohort. The panel discriminated pancreatic cancer cases from matched controls in blood specimens obtained between 7 and 13 mo prior to the development of symptoms and clinical diagnosis of pancreatic cancer. Conclusions Our findings indicate that GEM models of cancer, in combination with in-depth proteomic analysis, provide a useful strategy to identify candidate markers applicable to human cancer with potential utility for early detection. PMID:18547137

Pancreatic cystic tumors.

PubMed

Salvia, R; Festa, L; Butturini, G; Tonsi, A; Sartori, N; Biasutti, C; Capelli, P; Pederzoli, P

2004-04-01

Cystic tumors of the pancreas are less frequent than other tumors in neoplastic pancreatic pathology, but in recent years the literature has reported an increasing number. After the first report by Becourt in 1830, cystic tumors were classified into 2 different types by Compagno and Oertel in 1978: benign tumors with glycogen-rich cells and mucinous cystic neoplasms with overt and latent malignancy. The WHO classification of exocrine tumors of the pancreas, published in 1996, is based on the histopathological features of the epithelial wall, which are the main factor in differential diagnosis with cystic lesions of the pancreas. Thanks to the knowledge acquired up to now, a surgical procedure is not always required because the therapeutic choice is conditioned by the correct classification of this heterogeneous group of tumors. Clinical signs are not really useful in the clinical work up, most patients have no symptoms and when clinical signs are present, they may help us to pinpoint the organ of origin but never to identify the type of pathology. In the last few years, the great improvement in imaging has enabled us not only to discriminate cystic from solid lesions, but also to identify the features of the lesions and label them preoperatively. More invasive diagnostic procedures such as fine needle aspiration and intracystic fluid tumor marker level are not really useful because they are not sensitive and the cystic wall can show different degrees of dysplasia and de-epithelialization. These are the reasons for sending the entire specimen to pathology. Good cooperation between surgeons, pathologists, radiologists and gastroenterologists is mandatory to increase the chances of making a proper diagnosis. Therefore, we must analyze all the information we have, such as age, sex, clinical history, location of the tumor and radiological features, in order to avoid the mistake of treating a cystic neoplasm as a benign lesion or as a pseudocyst, as described in the

Gene expression profiles in primary pancreatic tumors and metastatic lesions of Ela-c-myc transgenic mice.

PubMed

Thakur, Archana; Bollig, Aliccia; Wu, Jiusheng; Liao, Dezhong J

2008-01-24

Pancreatic carcinoma usually is a fatal disease with no cure, mainly due to its invasion and metastasis prior to diagnosis. We analyzed the gene expression profiles of paired primary pancreatic tumors and metastatic lesions from Ela-c-myc transgenic mice in order to identify genes that may be involved in the pancreatic cancer progression. Differentially expressed selected genes were verified by semi-quantitative and quantitative RT-PCR. To further evaluate the relevance of some of the selected differentially expressed genes, we investigated their expression pattern in human pancreatic cancer cell lines with high and low metastatic potentials. Data indicate that genes involved in posttranscriptional regulation were a major functional category of upregulated genes in both primary pancreatic tumors (PT) and liver metastatic lesions (LM) compared to normal pancreas (NP). In particular, differential expression for splicing factors, RNA binding/pre-mRNA processing factors and spliceosome related genes were observed, indicating that RNA processing and editing related events may play critical roles in pancreatic tumor development and progression. High expression of insulin growth factor binding protein-1 (Igfbp1) and Serine proteinase inhibitor A1 (Serpina1), and low levels or absence of Wt1 gene expression were exclusive to liver metastatic lesion samples. We identified Igfbp1, Serpina1 and Wt1 genes that are likely to be clinically useful biomarkers for prognostic or therapeutic purposes in metastatic pancreatic cancer, particularly in pancreatic cancer where c-Myc is overexpressed.

APC promoter is frequently methylated in pancreatic juice of patients with pancreatic carcinomas or periampullary tumors.

PubMed

Ginesta, Mireia M; Diaz-Riascos, Zamira Vanessa; Busquets, Juli; Pelaez, Núria; Serrano, Teresa; Peinado, Miquel Àngel; Jorba, Rosa; García-Borobia, Francisco Javier; Capella, Gabriel; Fabregat, Joan

2016-09-01

Early detection of pancreatic and periampullary neoplasms is critical to improve their clinical outcome. The present authors previously demonstrated that DNA hypermethylation of adenomatous polyposis coli (APC), histamine receptor H2 (HRH2), cadherin 13 (CDH13), secreted protein acidic and cysteine rich (SPARC) and engrailed-1 (EN-1) promoters is frequently detected in pancreatic tumor cells. The aim of the present study was to assess their prevalence in pancreatic juice of carcinomas of the pancreas and periampullary area. A total of 135 pancreatic juices obtained from 85 pancreatic cancer (PC), 26 ampullary carcinoma (AC), 10 intraductal papillary mucinous neoplasm (IPMN) and 14 chronic pancreatitis (CP) patients were analyzed. The methylation status of the APC, HRH2, CDH13, SPARC and EN-1 promoters was analyzed using methylation specific-melting curve analysis (MS-MCA). Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were also tested with allele-specific quantitative polymerase chain reaction amplification. Out of the 5 promoters analyzed, APC (71%) and HRH2 (65%) were the most frequently methylated in PC juice. APC methylation was also detected at a high frequency in AC (76%) and IPMN (80%), but only occasionally observed in CP (7%). APC methylation had a high sensitivity (71-80%) for all types of cancer analyzed. The panel (where a sample scored as positive when ≥2 markers were methylated) did not outperform APC as a single marker. Finally, KRAS detection in pancreatic juice offered a lower sensitivity (50%) and specificity (71%) for detection of any cancer. APC hypermethylation in pancreatic juice, as assessed by MS-MCA, is a frequent event of potential clinical usefulness in the diagnosis of pancreatic and periampullary neoplasms.

Maintaining tumor targeting accuracy in real-time motion compensation systems for respiration-induced tumor motion.

PubMed

Malinowski, Kathleen; McAvoy, Thomas J; George, Rohini; Dieterich, Sonja; D'Souza, Warren D

2013-07-01

To determine how best to time respiratory surrogate-based tumor motion model updates by comparing a novel technique based on external measurements alone to three direct measurement methods. Concurrently measured tumor and respiratory surrogate positions from 166 treatment fractions for lung or pancreas lesions were analyzed. Partial-least-squares regression models of tumor position from marker motion were created from the first six measurements in each dataset. Successive tumor localizations were obtained at a rate of once per minute on average. Model updates were timed according to four methods: never, respiratory surrogate-based (when metrics based on respiratory surrogate measurements exceeded confidence limits), error-based (when localization error ≥ 3 mm), and always (approximately once per minute). Radial tumor displacement prediction errors (mean ± standard deviation) for the four schema described above were 2.4 ± 1.2, 1.9 ± 0.9, 1.9 ± 0.8, and 1.7 ± 0.8 mm, respectively. The never-update error was significantly larger than errors of the other methods. Mean update counts over 20 min were 0, 4, 9, and 24, respectively. The same improvement in tumor localization accuracy could be achieved through any of the three update methods, but significantly fewer updates were required when the respiratory surrogate method was utilized. This study establishes the feasibility of timing image acquisitions for updating respiratory surrogate models without direct tumor localization.

Acute pancreatitis associated with administration of a nitric oxide synthase inhibitor in tumor-bearing dogs.

PubMed

Poulson, J M; Dewhirst, M W; Gaskin, A A; Vujaskovic, Z; Samulski, T V; Prescott, D M; Meyer, R E; Page, R L; Thrall, D E

2000-01-01

Nitric oxide synthase (NOS) inhibitors have been investigated as potential cytotoxic agents to treat tumors lacking p53 function. Furthermore, their ability to reduce tumor blood flow can be combined with drugs that are specifically designed to kill cells that are hypoxic or to improve temperatures during local heat (hyperthermia) treatment of tumors. This paper reports the unexpected development of acute pancreatitis in two tumor-bearing pet dogs that were treated with the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) during administration of local hyperthermia. Prior to the use of L-NAME in tumor-bearing dogs, purpose-bred beagles were studied. Following induction of inhalation anesthesia, local hyperthermia was applied to either normal thigh muscle (beagles) or tumors (tumor-bearing dogs). Once a thermal steady state was achieved, L-NAME was administered and temperature monitoring continued. Animals were observed after treatment for evidence of toxicity. The beagles tolerated the treatment well, with no side effects noted either clinically or by routine CBC or blood chemistry analyses. In contrast, the first two tumor-bearing dogs accrued onto the phase I study developed acute pancreatitis in the immediate post-treatment period which necessitated hospitalization and intensive care. The trial was stopped. Both dogs had intercurrent risk factors which predisposed them to development of pancreatitis, although neither had a history of symptoms of pancreatitis at the time the hyperthermia + L-NAME treatment was given. We conclude that caution should be exercised when considering NOS inhibition for cancer treatment. Careful evaluation of history and health status as well as recognition of potential risk factors may be key in avoiding potentially fatal complications. This study demonstrates the value of performing potentially harmful treatments in tumor-bearing dogs prior to introduction into the human clinic.

Salinomycin nanoparticles interfere with tumor cell growth and the tumor microenvironment in an orthotopic model of pancreatic cancer.

PubMed

Daman, Zahra; Faghihi, Homa; Montazeri, Hamed

2018-05-02

Recently, salinomycin (SAL) has been reported to inhibit proliferation and induce apoptosis in various tumors. The aim of this study was to deliver SAL to orthotopic model of pancreatic cancer by the aid of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). The NPs were physico-chemically characterized and evaluated for cytotoxicity on luciferase-transduced AsPC-1 cells in vitro as well as implanted orthotopically into the pancreas of nude mice. SAL (3.5 mg/kg every other day) blocked tumor growth by 52% compared to the control group after 3 weeks of therapy. Western blotting of tumor protein extracts indicated that SAL treatment leads to up-regulation of E-cadherin, β-catenin, and transforming growth factor beta receptor (TGFβR) expressions in AsPC-1 orthotopic tumor. Noteworthy, immunofluorescence staining of adjacent tumor sections showed that treatment with SAL NPs cause significant apoptosis in the tumor cells rather than the stroma. Further investigations also revealed that TGFβR2 over-expression was induced in stroma cells after treatment with SAL NPs. These results highlight SAL-loaded PLGA NPs as a promising system for pancreatic cancer treatment, while the mechanistic questions need to be subsequently tested.

Evaluation of diagnostic cytology via endoscopic naso-pancreatic drainage for pancreatic tumor

PubMed Central

Iwata, Tomoyuki; Kitamura, Katsuya; Yamamiya, Akira; Ishii, Yu; Sato, Yoshiki; Nomoto, Tomohiro; Ikegami, Akitoshi; Yoshida, Hitoshi

2014-01-01

AIM: To evaluate the usefulness of cytology of the pancreatic juice obtained via the endoscopic naso-pancreatic drainage tube (ENPD-C). METHODS: ENPD was performed in cases where a diagnosis could not be made other than by using endoscopic retrograde cholangiopancreatography and in cases of pancreatic neoplasms or cystic tumors, including intraductal papillary mucinous neoplasm (IPMN) suspected to have malignant potential. 35 patients (21 males and 14 females) underwent ENPD between January 2007 and June 2013. The pancreatic duct was imaged and the procedure continued in one of ENPD-C or ENPD-C plus brush cytology (ENPD-BC). We checked the cytology result and the final diagnosis. RESULTS: The mean patient age was 69 years (range, 48-86 years). ENPD-C was performed in 24 cases and ENPD-C plus brush cytology (ENPD-BC) in 11 cases. The ENPD tube was inserted for an average of 3.5 d. The final diagnosis was confirmed on the basis of the resected specimen in 18 cases and of follow-up findings at least 6 mo after ENPD in the 18 inoperable cases. Malignancy was diagnosed in 21 cases and 14 patients were diagnosed as having a benign condition. The ratios of class V/IV:III:II/I findings were 7:7:7 in malignant cases and 0:3:11 in benign cases. The sensitivity and specificity for all patients were 33.3% and 100%, respectively. The cytology-positive rate was 37.5% (6/16) for pancreatic cancer. For IPMN cases, the sensitivity and specificity were 33% and 100%, respectively. CONCLUSION: Sensitivity may be further increased by adding brush cytology. Although we can diagnosis cancer in cases of a positive result, the accuracy of ENPD-C remains unsatisfactory. PMID:25132920

Clinical Use of High-Intensity Focused Ultrasound (HIFU) for Tumor and Pain Reduction in Advanced Pancreatic Cancer.

PubMed

Strunk, H M; Henseler, J; Rauch, M; Mücke, M; Kukuk, G; Cuhls, H; Radbruch, L; Zhang, L; Schild, H H; Marinova, M

2016-07-01

Evaluation of ultrasound-guided high-intensity focused ultrasound (HIFU) used for the first time in Germany in patients with inoperable pancreatic cancer for reduction of tumor volume and relief of tumor-associated pain. 15 patients with locally advanced inoperable pancreatic cancer and tumor-related pain symptoms were treated by HIFU (n = 6 UICC stage III, n = 9 UICC stage IV). 13 patients underwent simultaneous standard chemotherapy. Ablation was performed using the JC HIFU system (Chongqing, China HAIFU Company) with an ultrasonic device for real-time imaging. Imaging follow-up (US, CT, MRI) and clinical assessment using validated questionnaires (NRS, BPI) was performed before and up to 15 months after HIFU. Despite biliary or duodenal stents (4/15) and encasement of visceral vessels (15/15), HIFU treatment was performed successfully in all patients. Treatment time and sonication time were 111 min and 1103 s, respectively. The applied total energy was 386 768 J. After HIFU ablation, contrast-enhanced imaging showed devascularization of treated tumor regions with a significant average volume reduction of 63.8 % after 3 months. Considerable pain relief was achieved in 12 patients after HIFU (complete or partial pain reduction in 6 patients). US-guided HIFU with a suitable acoustic pathway can be used for local tumor control and relief of tumor-associated pain in patients with locally advanced pancreatic cancer. • US-guided HIFU allows an additive treatment of unresectable pancreatic cancer.• HIFU can be used for tumor volume reduction.• Using HIFU, a significant reduction of cancer-related pain was achieved.• HIFU provides clinical benefit in patients with pancreatic cancer. Citation Format: • Strunk HM, Henseler J, Rauch M et al. Clinical Use of High-Intensity Focused Ultrasound (HIFU) for Tumor and Pain Reduction in Advanced Pancreatic Cancer. Fortschr Röntgenstr 2016; 188: 662 - 670. © Georg Thieme Verlag KG

Expression of MUC1, MUC2, MUC3 and MUC4 mucin mRNAs in human pancreatic and intestinal tumor cell lines.

PubMed

Hollingsworth, M A; Strawhecker, J M; Caffrey, T C; Mack, D R

1994-04-15

We examined the steady-state expression levels of mRNA for the MUC1, MUC2, MUC3 and MUC4 gene products in 12 pancreatic tumor cell lines, 6 colon tumor cell lines, and one ileocecal tumor cell line. The results showed that 10 of 12 pancreatic tumor cell lines expressed MUC1 mRNA and that 7 of these 12 lines also expressed relatively high levels of MUC4 mRNA. In contrast, MUC2 mRNA was expressed at only low levels and MUC3 was not detected in the pancreatic tumor cell lines. All 7 intestinal tumor cell lines examined expressed MUC2, and 5 of 7 expressed MUC3; however only one expressed significant levels of MUC1 and 2 expressed low levels of MUC4 mRNA. This report of high levels of MUC4 mRNA expression by pancreatic tumor cells raises the possibility that mucin carbohydrate epitopes defined by antibodies such as DuPan 2 may be expressed on a second mucin core protein produced by pancreatic tumor cells.

Maintaining tumor targeting accuracy in real-time motion compensation systems for respiration-induced tumor motion

PubMed Central

Malinowski, Kathleen; McAvoy, Thomas J.; George, Rohini; Dieterich, Sonja; D’Souza, Warren D.

2013-01-01

Purpose: To determine how best to time respiratory surrogate-based tumor motion model updates by comparing a novel technique based on external measurements alone to three direct measurement methods. Methods: Concurrently measured tumor and respiratory surrogate positions from 166 treatment fractions for lung or pancreas lesions were analyzed. Partial-least-squares regression models of tumor position from marker motion were created from the first six measurements in each dataset. Successive tumor localizations were obtained at a rate of once per minute on average. Model updates were timed according to four methods: never, respiratory surrogate-based (when metrics based on respiratory surrogate measurements exceeded confidence limits), error-based (when localization error ≥3 mm), and always (approximately once per minute). Results: Radial tumor displacement prediction errors (mean ± standard deviation) for the four schema described above were 2.4 ± 1.2, 1.9 ± 0.9, 1.9 ± 0.8, and 1.7 ± 0.8 mm, respectively. The never-update error was significantly larger than errors of the other methods. Mean update counts over 20 min were 0, 4, 9, and 24, respectively. Conclusions: The same improvement in tumor localization accuracy could be achieved through any of the three update methods, but significantly fewer updates were required when the respiratory surrogate method was utilized. This study establishes the feasibility of timing image acquisitions for updating respiratory surrogate models without direct tumor localization. PMID:23822413

Abdominal organ motion during inhalation and exhalation breath-holds: pancreatic motion at different lung volumes compared.

PubMed

Lens, Eelco; Gurney-Champion, Oliver J; Tekelenburg, Daniël R; van Kesteren, Zdenko; Parkes, Michael J; van Tienhoven, Geertjan; Nederveen, Aart J; van der Horst, Astrid; Bel, Arjan

2016-11-01

Contrary to what is commonly assumed, organs continue to move during breath-holding. We investigated the influence of lung volume on motion magnitude during breath-holding and changes in velocity over the duration of breath-holding. Sixteen healthy subjects performed 60-second inhalation breath-holds in room-air, with lung volumes of ∼100% and ∼70% of the inspiratory capacity, and exhalation breath-holds, with lung volumes of ∼30% and ∼0% of the inspiratory capacity. During breath-holding, we obtained dynamic single-slice magnetic-resonance images with a time-resolution of 0.6s. We used 2-dimensional image correlation to obtain the diaphragmatic and pancreatic velocity and displacement during breath-holding. Organ velocity was largest in the inferior-superior direction and was greatest during the first 10s of breath-holding, with diaphragm velocities of 0.41mm/s, 0.29mm/s, 0.16mm/s and 0.15mm/s during BH 100% , BH 70% , BH 30% and BH 0% , respectively. Organ motion magnitudes were larger during inhalation breath-holds (diaphragm moved 9.8 and 9.0mm during BH 100% and BH 70% , respectively) than during exhalation breath-holds (5.6 and 4.3mm during BH 30% and BH 0% , respectively). Using exhalation breath-holds rather than inhalation breath-holds and delaying irradiation until after the first 10s of breath-holding may be advantageous for irradiation of abdominal tumors. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer

PubMed Central

Tan, Marcus C. B.; Goedegebuure, Peter S.; Belt, Brian A.; Flaherty, Brian; Sankpal, Narendra; Gillanders, William E.; Eberlein, Timothy J.; Hsieh, Chyi-Song; Linehan, David C.

2013-01-01

Tumors evade immune destruction by actively inducing immune tolerance through the recruitment of CD4+CD25+Foxp3+ regulatory T cells (Treg). We have previously described increased prevalence of these cells in pancreatic adenocarcinoma, but it remains unclear what mechanisms are involved in recruiting Treg into the tumor microenvironment. Here, we postulated that chemokines might direct Treg homing to tumor. We show, in both human pancreatic adenocarcinoma and a murine pancreatic tumor model (Pan02), that tumor cells produce increased levels of ligands for the CCR5 chemokine receptor, and, reciprocally, that CD4+ Foxp3+ Treg, compared with CD4+ Foxp3− effector T cells, preferentially express CCR5. When CCR5/CCL5 signaling is disrupted, either by reducing CCL5 production by tumor cells or by systemic administration of a CCR5 inhibitor (TAK-779), Treg migration to tumors is reduced and tumors are smaller than in control mice. Thus, this study demonstrates the importance of Treg in immune evasion by tumors, how blockade of Treg migration may inhibit tumor growth, and, specifically in pancreatic adenocarcinoma, the role of CCR5 in the homing of tumor-associated Treg. Selective targeting of CCR5/CCL5 signaling may represent a novel immunomodulatory strategy for the treatment of cancer. PMID:19155524

Telomerase activity is a useful marker to distinguish malignant pancreatic cystic tumors from benign neoplasms and pseudocysts.

PubMed

Yeh, T S; Cheng, A J; Chen, T C; Jan, Y Y; Hwang, T L; Jeng, L B; Chen, M F; Wang, T C

1999-12-01

Pancreatic serous cystadenoma, mucinous cystic neoplasms, ductal adenocarcinoma with cystic change, and pseudocysts are a spectrum of pancreatic cystic lesions. Their management strategy and prognosis are extremely diverse. Imaging study, cytology, and analysis of the tumor markers of cyst fluid are not always reliable in differentiation of these disease entities. Fifteen patients with pancreatic cystic neoplasms (including six mucinous cystadenocarcinomas, two mucinous cystic neoplasms with borderline malignancy, two mucinous cystadenomas, and five serous cystadenomas), 4 patients with pancreatic ductal adenocarcinomas with cystic change, and 10 patients with pseudocysts were studied. Echo-guided or computed tomography-guided biopsies of pancreatic cystic lesions and their normal counterparts were conducted on all patients prior to operation or other management. The specimens were assayed for telomerase activity by using TRAP (telomere repeat amplification protocol). The level of telomerase activity in each specimen was semiquantitated as strong, moderate, weak, and none. The final diagnoses were made from histopathological examination of surgically resected or biopsied specimens. The efficacy of telomerase activity as a tumor marker to predict malignancy of pancreatic cystic lesions was evaluated. Three of the four pancreatic ductal adenocarcinomas with cystic change had strong or moderate telomerase activity; four of the six mucinous cystadenocarcinomas had moderate or weak telomerase activity; one of the two mucinous cystadenomas with borderline malignancy had weak telomerase activity; and none of their normal counterparts had detectable telomerase activity. In contrast, none of the two mucinous cystadenomas, five serous cystadenomas, and 10 pseudocysts had detectable telomerase activity. Based on these results, the sensitivity of telomerase activity for prediction of malignancy or premalignancy of pancreatic cystic lesions was 67%, the specificity was 100

Characterization of a pancreatic islet cell tumor in a polar bear (Ursus maritimus).

PubMed

Fortin, Jessica S; Benoit-Biancamano, Marie-Odile

2014-01-01

Herein, we report a 25-year-old male polar bear suffering from a pancreatic islet cell tumor. The aim of this report is to present a case of this rare tumor in a captive polar bear. The implication of potential risk factors such as high carbohydrate diet or the presence of amyloid fibril deposits was assessed. Necropsy examination revealed several other changes, including nodules observed in the liver, spleen, pancreas, intestine, and thyroid glands that were submitted for histopathologic analysis. Interestingly, the multiple neoplastic nodules were unrelated and included a pancreatic islet cell tumor. Immunohistochemistry of the pancreas confirmed the presence of insulin and islet amyloid polypeptide (IAPP) within the pancreatic islet cells. The IAPP gene was extracted from the paraffin-embedded liver tissue and sequenced. IAPP cDNA from the polar bear exhibits some differences as compared to the sequence published for several other species. Different factors responsible for neoplasms in bears such as diet, infectious agents, and industrial chemical exposure are reviewed. This case report raised several issues that further studies may address by evaluating the prevalence of cancers in captive or wild animals. © 2014 Wiley Periodicals, Inc.

Characterization of pancreatic glucagon-producing tumors and pituitary gland tumors in transgenic mice overexpressing MYCN in hGFAP-positive cells.

PubMed

Fielitz, Kathrin; Althoff, Kristina; De Preter, Katleen; Nonnekens, Julie; Ohli, Jasmin; Elges, Sandra; Hartmann, Wolfgang; Klöppel, Günter; Knösel, Thomas; Schulte, Marc; Klein-Hitpass, Ludger; Beisser, Daniela; Reis, Henning; Eyking, Annette; Cario, Elke; Schulte, Johannes H; Schramm, Alexander; Schüller, Ulrich

2016-11-15

Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN-driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland. Pituitary tumors expressed chromogranin A and closely resembled human pituitary adenomas. Pancreatic tumors strongly produced and secreted glucagon, suggesting that they derived from glucagon- and GFAP-positive islet cells. Interestingly, 3 out of 9 human pancreatic neuroendocrine tumors expressed MYCN, supporting the similarity of the mouse tumors to the human system. Serial transplantations of mouse tumor cells into immunocompromised mice confirmed their fully transformed phenotype. MYCN-directed treatment by AuroraA- or Brd4-inhibitors resulted in significantly decreased cell proliferation in vitro and reduced tumor growth in vivo. In summary, we provide a novel mouse model for neuroendocrine tumors of the pancreas and pituitary gland that is dependent on MYCN expression and that may help to evaluate MYCN-directed therapies.

Targeted Disruption of Orchestration between Stroma and Tumor Cells in Pancreatic Cancer: Molecular Basis and Therapeutic Implications

PubMed Central

Kong, Xiangyu; Li, Lei; Li, Zhaoshen; Xie, Keping

2012-01-01

Pancreatic cancer is one of the most lethal malignancies, with a prominent desmoplastic reaction as the defining hallmark of the disease. The past several decades have seen dramatic progress in understanding of pancreatic cancer pathogenesis, including the identification of precursor lesions, sequential transformation from normal pancreas to invasive pancreatic cancer and corresponding signature genetic events, and the biological impact of those alterations on malignant behaviors. However, the current therapeutic strategies for epithelial tumor cells, which have exhibited potent antitumor activity in cell culture and animal models, have failed to have significant effects in the clinic. The desmoplastic stroma surrounding pancreatic cancer cells, which accounts for about 90% of a tumor’s mass, clearly is not a passive scaffold for cancer cells but an active contributor to carcinogenesis. Improved understanding of the dynamic interaction between cancer cells and their stroma will be important to designing new, effective therapeutic strategies for pancreatic cancer. This review focuses on the origination of stromal molecular and cellular components in pancreatic tumors, their biological effects on pancreatic cancer cells, and the orchestration between these two components. PMID:22749856

Dual role of Ski in pancreatic cancer cells: tumor-promoting versus metastasis-suppressive function.

PubMed

Wang, Peng; Chen, Zhen; Meng, Zhi-Qiang; Fan, Jie; Luo, Jian-Min; Liang, Wang; Lin, Jun-Hua; Zhou, Zhen-Hua; Chen, Hao; Wang, Kun; Shen, Ye-Hua; Xu, Zu-De; Liu, Lu-Ming

2009-09-01

Ski used to be defined as an oncogene that contributes to the resistance of tumor cells to transforming growth factor-beta (TGF-beta)-induced growth arrest. As TGF-beta has a dual effect on tumor growth with both tumor-suppressing and -promoting activity depending on the stage of carcinogenesis and the cell type, the precise role of Ski in carcinogenesis remains unclear. In this study, we show that downregulation of Ski through lentivirus-mediated RNA interference decreases tumor growth both in vitro and in vivo, yet promotes cell invasiveness in vitro, and lung metastasis in vivo in the pancreatic cancer cell line SW1990, which contain wild-type Smad4 expression, and the BxPC3 cell line, which is Smad4 deficient. We also show that the downregulation of Ski increases TGF-beta-induced transcriptional activity, which is associated with increased TGF-beta-dependent Smad2/3 phosphorylation, and results in an altered expression profile of TGF-beta-inducible genes involved in metastasis, angiogenesis and cell proliferation and epithelial-mesenchymal transition. Immunohistochemical analysis of specimens from 71 patients with pancreatic adenocarcinoma showed a significant association between overexpression of Ski and decreased patient survival time (P = 0.0024). Our results suggest that Ski may act as a tumor proliferation-promoting factor or as a metastatic suppressor in human pancreatic cancer.

Pancreatic Cancer Tumor Size on CT Scan Versus Pathologic Specimen: Implications for Radiation Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arvold, Nils D.; Niemierko, Andrzej; Mamon, Harvey J.

2011-08-01

Purpose: Pancreatic cancer primary tumor size measurements are often discordant between computed tomography (CT) and pathologic specimen after resection. Dimensions of the primary tumor are increasingly relevant in an era of highly conformal radiotherapy. Methods and Materials: We retrospectively evaluated 97 consecutive patients with resected pancreatic cancer at two Boston hospitals. All patients had CT scans before surgical resection. Primary endpoints were maximum dimension (in millimeters) of the primary tumor in any direction as reported by the radiologist on CT and by the pathologist for the resected gross fresh specimen. Endoscopic ultrasound (EUS) findings were analyzed if available. Results: Ofmore » the patients, 87 (90%) had preoperative CT scans available for review and 46 (47%) had EUS. Among proximal tumors (n = 69), 40 (58%) had pathologic duodenal invasion, which was seen on CT in only 3 cases. The pathologic tumor size was a median of 7 mm larger compared with CT size for the same patient (range, -15 to 43 mm; p < 0.0001), with 73 patients (84%) having a primary tumor larger on pathology than CT. Endoscopic ultrasound was somewhat more accurate, with pathologic tumor size being a median of only 5 mm larger compared with EUS size (range, -15 to 35 mm; p = 0.0003). Conclusions: Computed tomography scans significantly under-represent pancreatic cancer tumor size compared with pathologic specimens in resectable cases. We propose a clinical target volume expansion formula for the primary tumor based on our data. The high rate of pathologic duodenal invasion suggests a risk of duodenal undercoverage with highly conformal radiotherapy.« less

Dietary Fat Stimulates Pancreatic Cancer Growth and Promotes Fibrosis of the Tumor Microenvironment through the Cholecystokinin Receptor.

PubMed

Nadella, Sandeep; Burks, Julian; Al-Sabban, Abdulhameed; Inyang, Gloria; Wang, Juan; Tucker, Robin D; Zamanis, Marie E; Bukowski, William; Shivapurkar, Narayan; Smith, Jill P

2018-06-21

The gastrointestinal peptide cholecystokinin (CCK) is released from the duodenum in response to dietary fat to aid in digestion, and plasma CCK levels are elevated with the consumption of high fat diets. CCK is also a trophic peptide for the pancreas and has also been shown to stimulate growth of pancreatic cancer. In the current investigation, we studied the influence of a diet high in saturated fat on growth of pancreatic cancer in syngeneic murine models before the mice became obese to exclude the confounding factors associated with obesity. The high fat diet significantly increased growth and metastasis of pancreatic cancer compared to the control diet, and the stimulatory effect was blocked by the CCK-receptor antagonist proglumide. We then selectively knocked out the CCK receptor on the pancreatic cancer cells using CRISPR technology and showed that without CCK receptors, dietary fat was unable to stimulate cancer growth. Next we demonstrated that dietary fat failed to influence pancreatic cancer xenograft growth in genetically engineered CCK peptide knockout mice. The tumor associated fibrosis that is so prevalent in the pancreatic cancer microenvironment was significantly decreased with CCK receptor antagonist therapy since fibroblasts also have CCK receptors. The CCK receptor antagonist proglumide also altered tumor metalloprotease expression and increased tumor suppressor genes by a PCR array. Our studies confirm that a diet high in saturated fat promotes growth of pancreatic cancer and the action is mediated by the CCK- receptor pathway.

[A Case of Pancreatic Neuroendocrine Tumor with Necrolytic Migratory Erythema].

PubMed

Hijikawa, Takeshi; Kitade, Hiroaki; Yanagida, Hidesuke; Yamada, Masanori; Yoshioka, Kazuhiko; Shijimaya, Takako; Kiyohara, Takahiro; Uemura, Yoshiko; Kon, Masanori

2017-10-01

A 45-year-old man was admitted because of necrolytic migratory erythema. A computed tomographic scan of the abdomen revealed a 4.5cm mass in the tail of the pancreas. We performed distal pancreatectomy and splenectomy, and a definitive diagnosis of pancreatic neuroendocrine tumor(WHO class grade 2)was made histopathologically.

Pancreatic neuroendocrine tumor with complete replacement of the pancreas by serous cystic neoplasms in a patient with von Hippel-Lindau disease: a case report.

PubMed

Maeda, Shimpei; Motoi, Fuyuhiko; Oana, Shuhei; Ariake, Kyohei; Mizuma, Masamichi; Morikawa, Takanori; Hayashi, Hiroki; Nakagawa, Kei; Kamei, Takashi; Naitoh, Takeshi; Unno, Michiaki

2017-09-25

von Hippel-Lindau disease is a dominantly inherited multi-system syndrome with neoplastic hallmarks. Pancreatic lesions associated with von Hippel-Lindau include serous cystic neoplasms, simple cysts, and neuroendocrine tumors. The combination of pancreatic neuroendocrine tumors and serous cystic neoplasms is relatively rare, and the surgical treatment of these lesions must consider both preservation of pancreatic function and oncological clearance. We report a patient with von Hippel-Lindau disease successfully treated with pancreas-sparing resection of a pancreatic neuroendocrine tumor where the pancreas had been completely replaced by serous cystic neoplasms, in which pancreatic function was preserved. A 39-year-old female with von Hippel-Lindau disease was referred to our institution for treatment of a pancreatic neuroendocrine tumor. Abdominal computed tomography demonstrated a well-enhanced mass, 4 cm in diameter in the tail of the pancreas, and two multilocular tumors with several calcifications, 5 cm in diameter, in the head of the pancreas. There was complete replacement of the pancreas by multiple cystic lesions with diameters ranging from 1 to 3 cm. Magnetic resonance cholangiopancreatography showed innumerable cystic lesions on the whole pancreas and no detectable main pancreatic duct. Endoscopic ultrasound-guided fine-needle aspiration of the mass in the pancreatic tail showed characteristic features of a neuroendocrine tumor. A diagnosis of pancreatic neuroendocrine tumor in the tail of the pancreas and mixed-type serous cystic neoplasms replacing the whole pancreas was made and she underwent distal pancreatectomy while avoiding total pancreatectomy. The stump of the pancreas was sutured as firm as possible using a fish-mouth closure. The patient made a good recovery and was discharged on postoperative day 9. She is currently alive and well with no symptoms of endocrine or exocrine pancreatic insufficiency 8 months after surgery. A pancreas

Lung tumor motion prediction during lung brachytherapy using finite element model

NASA Astrophysics Data System (ADS)

Shirzadi, Zahra; Sadeghi Naini, Ali; Samani, Abbas

2012-02-01

A biomechanical model is proposed to predict deflated lung tumor motion caused by diaphragm respiratory motion. This model can be very useful for targeting the tumor in tumor ablative procedures such as lung brachytherapy. To minimize motion within the target lung, these procedures are performed while the lung is deflated. However, significant amount of tissue deformation still occurs during respiration due to the diaphragm contact forces. In the absence of effective realtime image guidance, biomechanical models can be used to estimate tumor motion as a function of diaphragm's position. To develop this model, Finite Element Method (FEM) was employed. To demonstrate the concept, we conducted an animal study of an ex-vivo porcine deflated lung with a tumor phantom. The lung was deformed by compressing a diaphragm mimicking cylinder against it. Before compression, 3D-CT image of this lung was acquired, which was segmented and turned into FE mesh. The lung tissue was modeled as hyperelastic material with a contact loading to calculate the lung deformation and tumor motion during respiration. To validate the results from FE model, the motion of a small area on the surface close to the tumor was tracked while the lung was being loaded by the cylinder. Good agreement was demonstrated between the experiment results and simulation results. Furthermore, the impact of tissue hyperelastic parameters uncertainties in the FE model was investigated. For this purpose, we performed in-silico simulations with different hyperelastic parameters. This study demonstrated that the FEM was accurate and robust for tumor motion prediction.

Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer.

PubMed

Yao, Jun; Zhang, Lu-Lin; Huang, Xu-Mei; Li, Wen-Yao; Gao, She-Gan

2017-06-07

To detect the expression of pleiotrophin (PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion (PNI). An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis. The expression rates of PTN and N-syndecan proteins were 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI ( P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites ( P = 0.009), liver metastasis ( P = 0.035), and decreased survival time ( P = 0.022). N-syndecan expression was significantly associated with tumor size ( P = 0.025), but not with survival time ( P = 0.539). High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer.

Isolation of circulating tumor cells from pancreatic cancer by automated filtration

PubMed Central

Brychta, Nora; Drosch, Michael; Driemel, Christiane; Fischer, Johannes C.; Neves, Rui P.; Esposito, Irene; Knoefel, Wolfram; Möhlendick, Birte; Hille, Claudia; Stresemann, Antje; Krahn, Thomas; Kassack, Matthias U.; Stoecklein, Nikolas H.; von Ahsen, Oliver

2017-01-01

It is now widely recognized that the isolation of circulating tumor cells based on cell surface markers might be hindered by variability in their protein expression. Especially in pancreatic cancer, isolation based only on EpCAM expression has produced very diverse results. Methods that are independent of surface markers and therefore independent of phenotypical changes in the circulating cells might increase CTC recovery also in pancreatic cancer. We compared an EpCAM-dependent (IsoFlux) and a size-dependent (automated Siemens Healthineers filtration device) isolation method for the enrichment of pancreatic cancer CTCs. The recovery rate of the filtration based approach is dramatically superior to the EpCAM-dependent approach especially for cells with low EpCAM-expression (filtration: 52%, EpCAM-dependent: 1%). As storage and shipment of clinical samples is important for centralized analyses, we also evaluated the use of frozen diagnostic leukapheresis (DLA) as source for isolating CTCs and subsequent genetic analysis such as KRAS mutation detection analysis. Using frozen DLA samples of pancreatic cancer patients we detected CTCs in 42% of the samples by automated filtration. PMID:29156783

Isolation of circulating tumor cells from pancreatic cancer by automated filtration.

PubMed

Brychta, Nora; Drosch, Michael; Driemel, Christiane; Fischer, Johannes C; Neves, Rui P; Esposito, Irene; Knoefel, Wolfram; Möhlendick, Birte; Hille, Claudia; Stresemann, Antje; Krahn, Thomas; Kassack, Matthias U; Stoecklein, Nikolas H; von Ahsen, Oliver

2017-10-17

It is now widely recognized that the isolation of circulating tumor cells based on cell surface markers might be hindered by variability in their protein expression. Especially in pancreatic cancer, isolation based only on EpCAM expression has produced very diverse results. Methods that are independent of surface markers and therefore independent of phenotypical changes in the circulating cells might increase CTC recovery also in pancreatic cancer. We compared an EpCAM-dependent (IsoFlux) and a size-dependent (automated Siemens Healthineers filtration device) isolation method for the enrichment of pancreatic cancer CTCs. The recovery rate of the filtration based approach is dramatically superior to the EpCAM-dependent approach especially for cells with low EpCAM-expression (filtration: 52%, EpCAM-dependent: 1%). As storage and shipment of clinical samples is important for centralized analyses, we also evaluated the use of frozen diagnostic leukapheresis (DLA) as source for isolating CTCs and subsequent genetic analysis such as KRAS mutation detection analysis. Using frozen DLA samples of pancreatic cancer patients we detected CTCs in 42% of the samples by automated filtration.

Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma.

PubMed

Zhao, Xianda; Fan, Wei; Xu, Zhigao; Chen, Honglei; He, Yuyu; Yang, Gui; Yang, Gang; Hu, Hanning; Tang, Shihui; Wang, Ping; Zhang, Zheng; Xu, Peipei; Yu, Mingxia

2016-12-06

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancer death reasons. Anti-tumor necrosis factor-alpha (TNF-α) antibodies have shown promising effects in PDAC pre-clinical models. However, the prognostic values of TNF-α, underlying mechanisms by which anti-TNF-α treatments inhibit PDAC, and potential synergistic effects of anti-TNF-α treatments with chemotherapy are still unclear. To identify the targeting values of TNF-α in PDAC, we measured TNF-α expression in different stages of PDAC initiation and evaluated its prognostic significance in a pancreatic cancer cohort. We found that TNF-α expression elevated in PDAC initiation process, and high expression of TNF-α was an independent prognostic marker of poor survival. We further evaluated anti-tumor effects of anti-TNF-α treatments in PDAC. Anti-TNF-α treatments resulted in decreased cell viability in both PDAC tumor cells and pancreatic satellite cells in similar dose in vitro. In vivo, anti-TNF-α treatments showed effects in reducing desmoplasia and the tumor promoting inflammatory microenvironment in PDAC. Combination of anti-TNF-α treatments with chemotherapy partly overcame chemoresistance of PDAC tumor cells and prolonged the survival of PDAC mouse model. In conclusion, our findings indicated that TNF-α in PDAC can be a prognostic and therapeutic target. Inhibition of TNF-α synergized with chemotherapy in PDAC resulted in better pre-clinical responses via killing tumor cells as well as diminishing desmoplasia and inflammation in PDAC tumor stroma.

A prospective assessment of the natural course of the exocrine pancreatic function in patients with a pancreatic head tumor.

PubMed

Sikkens, Edmée C M; Cahen, Djuna L; de Wit, Jill; Looman, Caspar W N; van Eijck, Casper; Bruno, Marco J

2014-01-01

In cancer of the pancreatic head region, exocrine insufficiency is a well-known complication, leading to steatorrhea, weight loss, and malnutrition. Its presence is frequently overlooked, however, because the primary attention is focused on cancer treatment. To date, the risk of developing exocrine insufficiency is unspecified. Therefore, we assessed this function in patients with tumors of the pancreatic head, distal common bile duct, or ampulla of Vater. Between March 2010 and August 2012, we prospectively included patients diagnosed with cancer of the pancreatic head region at our tertiary center. To preclude the effect of a resection, we excluded operated patients. Each month, the exocrine function was determined with a fecal elastase test. Furthermore, endocrine function, steatorrhea-related symptoms, and body weight were evaluated. Patients were followed for 6 months, or until death. Thirty-two patients were included. The tumor was located in the pancreas in 75%, in the bile duct in 16%, and in the ampullary region in 9%, with a median size of 2.5 cm. At diagnosis, the prevalence of exocrine insufficiency was 66%, which increased to 92% after a median follow-up of 2 months (interquartile range, 1 to 4 mo). Most patients with cancer of the pancreatic head region were already exocrine insufficient at diagnosis, and within several months, this function was impaired in almost all cases. Given this high prevalence, physicians should be focused on diagnosing and treating exocrine insufficiency, to optimize the nutritional status and physical condition, especially for those patients undergoing palliative chemotherapy and/or radiotherapy.

Development of an endoluminal high-intensity ultrasound applicator for image-guided thermal therapy of pancreatic tumors

NASA Astrophysics Data System (ADS)

Adams, Matthew S.; Scott, Serena J.; Salgaonkar, Vasant A.; Jones, Peter D.; Plata-Camargo, Juan C.; Sommer, Graham; Diederich, Chris J.

2015-03-01

An ultrasound applicator for endoluminal thermal therapy of pancreatic tumors has been introduced and evaluated through acoustic/biothermal simulations and ex vivo experimental investigations. Endoluminal therapeutic ultrasound constitutes a minimally invasive conformal therapy and is compatible with ultrasound or MR-based image guidance. The applicator would be placed in the stomach or duodenal lumen, and sonication would be performed through the luminal wall into the tumor, with concurrent water cooling of the wall tissue to prevent its thermal injury. A finite-element (FEM) 3D acoustic and biothermal model was implemented for theoretical analysis of the approach. Parametric studies over transducer geometries and frequencies revealed that operating frequencies within 1-3 MHz maximize penetration depth and lesion volume while sparing damage to the luminal wall. Patient-specific FEM models of pancreatic head tumors were generated and used to assess the feasibility of performing endoluminal ultrasound thermal ablation and hyperthermia of pancreatic tumors. Results indicated over 80% of the volume of small tumors (~2 cm diameter) within 35 mm of the duodenum could be safely ablated in under 30 minutes or elevated to hyperthermic temperatures at steady-state. Approximately 60% of a large tumor (~5 cm diameter) model could be safely ablated by considering multiple positions of the applicator along the length of the duodenum to increase coverage. Prototype applicators containing two 3.2 MHz planar transducers were fabricated and evaluated in ex vivo porcine carcass heating experiments under MR temperature imaging (MRTI) guidance. The applicator was positioned in the stomach adjacent to the pancreas, and sonications were performed for 10 min at 5 W/cm2 applied intensity. MRTI indicated over 400C temperature rise in pancreatic tissue with heating penetration extending 3 cm from the luminal wall.

Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice

PubMed Central

Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

2016-01-01

Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs

Pancreatic acinar cell carcinoma extending into the common bile and main pancreatic ducts.

PubMed

Yamaguchi, Rin; Okabe, Yoshinobu; Jimi, Atsuo; Shiota, Koji; Kodama, Takahito; Naito, Yoshiki; Yasunaga, Masafumi; Kinoshita, Hisafumi; Kojiro, Masamichi

2006-10-01

Acinar cell carcinoma (ACC) of the pancreas is relatively rare, accounting for only approximately 1% of all exocrine pancreatic tumors. A 69-year-old man was found to have a mass lesion measuring approximately 4 cm in diameter in the pancreatic head on ultrasound, abdominal dynamic CT, and percutaneous transhepatic cholangiography. Magnetic resonance cholangiopancreatography showed defect of the lower common bile duct (CBD) due to obstruction by the tumor cast. Histopathologically, the pancreatic head tumor invaded the main pancreatic duct (MPD) and CBD with extension into the CBD in a form of tumor cast. The tumor cells consisted of a solid proliferation with abundant eosinophilic cytoplasm and round nuclei in an acinar and trabecular fashion. A 55-year-old man with upper abdominal pain and nausea, had a cystic lesion approximately 3 cm in size in the pancreatic tail on CT. Histopathologically, the tumor was encapsulated by fibrous capsule and had extensive central necrosis with solid areas in the tumor periphery, and invaded with extension into the MPD in a form of tumor cast. The tumor cells resembled acinar cells in solid growths. Two resected cases of ACC with unusual tumor extension into the CBD and the MPD, respectively, are reported.

MUC1-specific CTLs are non-functional within a pancreatic tumor microenvironment.

PubMed

Mukherjee, P; Ginardi, A R; Madsen, C S; Tinder, T L; Jacobs, F; Parker, J; Agrawal, B; Longenecker, B M; Gendler, S J

2001-01-01

Pancreatic cancer is a highly aggressive, treatment refractory disease and is the fourth leading cause of death in the United States. In humans, 90% of pancreatic adenocarcinomas over-express altered forms of a tumor-associated antigen, MUC1 (an epithelial mucin glycoprotein), which is a target for immunotherapy. Using a clinically relevant mouse model of pancreas cancer that demonstrates peripheral and central tolerance to human MUC1 and develops spontaneous tumors of the pancreas, we have previously reported the presence of functionally active, low affinity, MUC1-specific precursor cytotoxic T cells (pCTLs). Hypothesis for this study is that MUC1-based immunization may enhance the low level MUC1-specific immunity that may lead to an effective anti-tumor response. Data demonstrate that MUC1 peptide-based immunization elicits mature MUC1-specific CTLs in the peripheral lymphoid organs. The mature CTLs secrete IFN-gamma and are cytolytic against MUC1-expressing tumor cells in vitro. However, active CTLs that infiltrate the pancreas tumor microenvironment become cytolytically anergic and are tolerized to MUC1 antigen, allowing the tumor to grow. We demonstrate that the CTL tolerance could be reversed at least in vitro with the use of anti-CD40 co-stimulation. The pancreas tumor cells secrete immunosuppressive cytokines, including IL-10 and TGF-beta that are partly responsible for the down-regulation of CTL activity. In addition, they down-regulate their MHC class I molecules to avoid immune recognition. CD4+ CD25+ T regulatory cells, which secrete IL-10, were also found in the tumor environment. Together these data indicate the use of several immune evasion mechanisms by tumor cells to evade CTL killing. Thus altering the tumor microenvironment to make it more conducive to CTL killing may be key in developing a successful anti-cancer immunotherapy.

The pancreatic niche inhibits the effectiveness of sunitinib treatment of pancreatic cancer

PubMed Central

Martínez-Bosch, Neus; Guerrero, Pedro Enrique; Moreno, Mireia; José, Anabel; Iglesias, Mar; Munné-Collado, Jessica; Anta, Héctor; Gibert, Joan; Orozco, Carlos Alberto; Vinaixa, Judith; Fillat, Cristina; Viñals, Francesc; Navarro, Pilar

2016-01-01

Current treatments for pancreatic ductal adenocarcinoma (PDA) are ineffective, making this the 4th leading cause of cancer deaths. Sunitinib is a broad-spectrum inhibitor of tyrosine kinase receptors mostly known for its anti-angiogenic effects. We tested the therapeutic effects of sunitinib in pancreatic cancer using the Ela-myc transgenic mouse model. We showed that Ela-myc pancreatic tumors express PDGFR and VEGFR in blood vessels and epithelial cells, rendering these tumors sensitive to sunitinib by more than only its anti-angiogenic activity. However, sunitinib treatment of Ela-myc mice with either early or advanced tumor progression had no impact on either survival or tumor burden. Further histopathological characterization of these tumors did not reveal differences in necrosis, cell differentiation, angiogenesis, apoptosis or proliferation. In stark contrast, in vitro sunitinib treatment of Ela-myc– derived cell lines showed high sensitivity to the drug, with increased apoptosis and reduced proliferation. Correspondingly, subcutaneous tumors generated from these cell lines completely regressed in vivo after sunitinib treatments. These data point at the pancreatic tumor microenvironment as the most likely barrier preventing sunitinib treatment efficiency in vivo. Combined treatments with drugs that disrupt tumor fibrosis may enhance sunitinib therapeutic effectiveness in pancreatic cancer treatment. PMID:27374084

Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response To Promote a Tumor-Tolerant Immune Microenvironment

PubMed Central

Delitto, Daniel; Delitto, Andrea E.; DiVita, Bayli B.; Pham, Kien; Han, Song; Hartlage, Emily R.; Newby, Brittney N.; Gerber, Michael H.; Behrns, Kevin E.; Moldawer, Lyle L.; Thomas, Ryan M.; George, Thomas J.; Brusko, Todd M.; Mathews, Clayton E.; Liu, Chen; Trevino, Jose G.; Hughes, Steven J.; Wallet, Shannon M.

2016-01-01

Cancer cells exert mastery over the local tumor-associated stroma (TAS) to configure protective immunity within the tumor microenvironment. The immunomodulatory character of pancreatic lysates of patients with cancer differs from those with pancreatitis. In this study, we evaluated the crosstalk between pancreatic cancer (PC) and its TAS in primary human cell culture models. Upon exposure of TAS to PC cell-conditioned media, we documented robust secretion of IL-6 and IL-8. This TAS response was MyD88-dependent and sufficient to directly suppress both CD4+ and CD8+ T cell proliferation, inducing Th17 polarization at the expense of Th1. We found that patients possessed a similar shift in circulating effector memory Th17:Th1 ratios compared to healthy controls. The TAS response also directly suppressed CD8+ T cell-mediated cytotoxicity. Overall, our results demonstrate how TAS contributes to the production of an immunosuppressive tumor microenvironment in pancreatic cancer. PMID:27864347

Curcumin Analogue CDF Inhibits Pancreatic Tumor Growth by Switching on Suppressor microRNAs and Attenuating EZH2 Expression

PubMed Central

Bao, Bin; Ali, Shadan; Banerjee, Sanjeev; Wang, Zhiwei; Logna, Farah; Azmi, Asfar S.; Kong, Dejuan; Ahmad, Aamir; Li, Yiwei; Padhye, Subhash; Sarkar, Fazlul H.

2013-01-01

The histone methyltransferase EZH2 is a central epigenetic regulator of cell survival, proliferation, and cancer stem cell (CSC) function. EZH2 expression is increased in various human cancers, including highly aggressive pancreatic cancers, but the mechanisms underlying for its biologic effects are not yet well understood. In this study, we probed EZH2 function in pancreatic cancer using diflourinated-curcumin (CDF), a novel analogue of the turmeric spice component curcumin that has antioxidant properties. CDF decreased pancreatic cancer cell survival, clonogenicity, formation of pancreatospheres, invasive cell migration, and CSC function in human pancreatic cancer cells. These effects were associated with decreased expression of EZH2 and increased expression of a panel of tumor-suppressive microRNAs (miRNA), including let-7a,b,c,d, miR-26a, miR-101, miR-146a, and miR-200b,c that are typically lost in pancreatic cancer. Mechanistic investigations revealed that reexpression of miR-101 was sufficient to limit the expression of EZH2 and the proinvasive cell surface adhesion molecule EpCAM. In an orthotopic xenograft model of human pancreatic cancer, administration of CDF inhibited tumor growth in a manner associated with reduced expression of EZH2, Notch-1, CD44, EpCAM, and Nanog and increased expression of let-7, miR-26a, and miR-101. Taken together, our results indicated that CDF inhibited pancreatic cancer tumor growth and aggressiveness by targeting an EZH2-miRNA regulatory circuit for epigenetically controlled gene expression. PMID:22108826

Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer

PubMed Central

Yao, Jun; Zhang, Lu-Lin; Huang, Xu-Mei; Li, Wen-Yao; Gao, She-Gan

2017-01-01

AIM To detect the expression of pleiotrophin (PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion (PNI). METHODS An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis. RESULTS The expression rates of PTN and N-syndecan proteins were 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI (P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites (P = 0.009), liver metastasis (P = 0.035), and decreased survival time (P = 0.022). N-syndecan expression was significantly associated with tumor size (P = 0.025), but not with survival time (P = 0.539). CONCLUSION High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer. PMID:28638231

Middle-preserving pancreatectomy for advanced transverse colon cancer invading the duodenun and non-functioning endocrine tumor in the pancreatic tail.

PubMed

Noda, Hiroshi; Kato, Takaharu; Kamiyama, Hidenori; Toyama, Nobuyuki; Konishi, Fumio

2011-02-01

A 73-year-old female was referred to our hospital with a diagnosis of advanced transverse colon cancer with severe anemia and body weight loss. Preoperative evaluations, including colonoscopy, gastroduodenoscopy, and computed tomography, revealed not only a transverse colon cancer massively invading the duodenum, but also a non-functioning endocrine tumor in the pancreatic tail. We performed middle-preserving pancreatectomy (MPP) with right hemicolectomy for these tumors with a curative intent. After the resection, about 6 cm of the body of the pancreas was preserved, and signs of diabetes mellitus have not appeared. The postoperative course was complicated by a grade B pancreatic fistula, but this was successfully treated with conservative management. After a 33-day hospital stay, the patient returned to daily life without signs of pancreatic exocrine insufficiency. Although the long-term follow-up of the patient is indispensable, in this case, MPP might be able to lead to the curative resection of transverse colon cancer massively invading the duodenum and non-functioning endocrine tumor in the pancreatic tail with preservation of pancreatic function.

c-Jun N-terminal kinase in pancreatic tumor stroma augments tumor development in mice.

PubMed

Sato, Takeshi; Shibata, Wataru; Hikiba, Yohko; Kaneta, Yoshihiro; Suzuki, Nobumi; Ihara, Sozaburo; Ishii, Yasuaki; Sue, Soichiro; Kameta, Eri; Sugimori, Makoto; Yamada, Hiroaki; Kaneko, Hiroaki; Sasaki, Tomohiko; Ishii, Tomohiro; Tamura, Toshihide; Kondo, Masaaki; Maeda, Shin

2017-11-01

Pancreatic ductal adenocarcinoma (PDAC) is a life-threatening disease and there is an urgent need to develop improved therapeutic approaches. The role of c-Jun N-terminal kinase (JNK) in PDAC stroma is not well defined even though dense desmoplastic reactions are characteristic of PDAC histology. We aimed to explore the role of JNK in PDAC stroma in mice. We crossed Ptf1a Cre/+ ;Kras G12D/+ mice with JNK1 -/- mice to generate Ptf1a Cre/+ ;Kras G12D/+ ;JNK1 -/- (Kras;JNK1 -/- ) mice. Tumor weight was significantly lower in Kras;JNK1 -/- mice than in Kras;JNK1 +/- mice, whereas histopathological features were similar. We also transplanted a murine PDAC cell line (mPC) with intact JNK1 s.c. into WT and JNK1 -/- mice. Tumor diameters were significantly smaller in JNK1 -/- mice. Phosphorylated JNK (p-JNK) was activated in α-smooth muscle actin (SMA)-positive cells in tumor stroma, and mPC-conditioned medium activated p-JNK in tumor-associated fibroblasts (TAF) in vitro. Relative expression of Ccl20 was downregulated in stimulated TAF. Ccl20 is an important chemokine that promotes CD8 + T-cell infiltration by recruitment of dendritic cells, and the number of CD8 + T cells was decreased in Kras;JNK1 +/- mice compared with Kras;JNK1 -/- mice. These results suggest that the cancer secretome decreases Ccl20 secretion from TAF by activation of JNK, and downregulation of Ccl20 secretion might be correlated with reduction of infiltrating CD8 + T cells. Therefore, we concluded that inhibition of activated JNK in pancreatic tumor stroma could be a potential therapeutic target to increase Ccl20 secretion from TAF and induce accumulation of CD8 + T cells, which would be expected to enhance antitumor immunity. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Pancreatic non-functioning neuroendocrine tumor: a new entity genetically related to Lynch syndrome

PubMed Central

Serracant Barrera, Anna; Serra Pla, Sheila; Blázquez Maña, Carmen María; Salas, Rubén Carrera; García Monforte, Neus; Bejarano González, Natalia; Romaguera Monzonis, Andreu; Andreu Navarro, Francisco Javier; Bella Cueto, Maria Rosa

2017-01-01

Some pancreatic neuroendocrine tumors (P-NETs) are associated with hereditary syndromes. An association between Lynch syndrome (LS) and P-NETs has been suggested, however it has not been confirmed to date. We describe the first case associating LS and P-NETs. Here we report a 65-year-old woman who in the past 20 years presented two colorectal carcinomas (CRC) endometrial carcinoma (EC), infiltrating ductal breast carcinoma, small intestine adenocarcinoma, two non-functioning P-NETs and sebomatricoma. With the exception of one P-NET, all these conditions were associated with LS, as confirmed by immunohistochemistry (IHC) and polymerase chain reaction (PCR). LS is caused by a mutation of a mismatch repair (MMR) gene which leads to a loss of expression of its protein. CRC is the most common tumor, followed by EC. Pancreatic tumors have also been associated with LS. Diagnosis of LS is based on clinical criteria (Amsterdam II and Bethesda) and genetic study (MMR gene mutation). The association between LS and our patient’s tumors was confirmed by IHC (loss of expression of proteins MLH1 and its dimer PMS2) and the detection of microsatellite instability (MSI) using PCR. PMID:29184699

Biochemical analysis of secretory proteins synthesized by normal rat pancreas and by pancreatic acinar tumor cells

PubMed Central

1982-01-01

We have examined the secretogogue responsiveness and the pattern of secretory proteins produced by a transplantable rat pancreatic acinar cell tumor. Dispersed tumor cells were found to discharge secretory proteins in vitro when incubated with hormones that act on four different classes of receptors: carbamylcholine, caerulein, secretin- vasoactive intestinal peptide, and bombesin. With all hormones tested, maximal discharge from tumor cells was only about one-half that of control pancreatic lobules, but occurred at the same dose optima except for secretin, whose dose optimum was 10-fold higher. Biochemical analysis of secretory proteins discharged by the tumor cells was carried out by crossed immunoelectrophoresis and by two-dimensional isoelectric focusing-SDS polyacrylamide gel electrophoresis. To establish a baseline for comparison, secretory proteins from normal rat pancreas were identified according to enzymatic activity and correlated with migration position on two-dimensional gels. Our results indicate that a group of basic polypeptides including proelastase, basic trypsinogen, basic chymotrypsinogen, and ribonuclease, two out of three forms of procarboxypeptidase B, and the major lipase species were greatly reduced or absent in tumor cell secretion. In contrast, the amount of acidic chymotrypsinogen was notably increased compared with normal acinar cells. Although the acinar tumor cells are highly differentiated cytologically and express functional receptors for several classes of pancreatic secretagogues, they show quantitative and qualitative differences when compared with normal pancreas with regard to their production of secretory proteins. PMID:6185502

Pancreatic tumor cell metabolism: focus on glycolysis and its connected metabolic pathways.

PubMed

Guillaumond, Fabienne; Iovanna, Juan Lucio; Vasseur, Sophie

2014-03-01

Because of lack of effective treatment, pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death by cancer in Western countries, with a very weak improvement of survival rate over the last 40years. Defeat of numerous conventional therapies to cure this cancer makes urgent to develop new tools usable by clinicians for a better management of the disease. Aggressiveness of pancreatic cancer relies on its own hallmarks: a low vascular network as well as a prominent stromal compartment (desmoplasia), which creates a severe hypoxic environment impeding correct oxygen and nutrients diffusion to the tumoral cells. To survive and proliferate in those conditions, pancreatic cancer cells set up specific metabolic pathways to meet their tremendous energetic and biomass demands. However, as PDAC is a heterogenous tumor, a complex reprogramming of metabolic processes is engaged by cancer cells according to their level of oxygenation and nutrients supply. In this review, we focus on the glycolytic activity of PDAC and the glucose-connected metabolic pathways which contribute to the progression and dissemination of this disease. We also discuss possible therapeutic strategies targeting these pathways in order to cure this disease which still until now is resistant to numerous conventional treatments. Copyright © 2014 Elsevier Inc. All rights reserved.

Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma

PubMed Central

Xu, Zhigao; Chen, Honglei; He, Yuyu; Yang, Gui; Yang, Gang; Hu, Hanning; Tang, Shihui; Wang, Ping; Zhang, Zheng; Xu, Peipei; Yu, Mingxia

2016-01-01

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancer death reasons. Anti-tumor necrosis factor-alpha (TNF-α) antibodies have shown promising effects in PDAC pre-clinical models. However, the prognostic values of TNF-α, underlying mechanisms by which anti-TNF-α treatments inhibit PDAC, and potential synergistic effects of anti-TNF-α treatments with chemotherapy are still unclear. Results and Methods To identify the targeting values of TNF-α in PDAC, we measured TNF-α expression in different stages of PDAC initiation and evaluated its prognostic significance in a pancreatic cancer cohort. We found that TNF-α expression elevated in PDAC initiation process, and high expression of TNF-α was an independent prognostic marker of poor survival. We further evaluated anti-tumor effects of anti-TNF-α treatments in PDAC. Anti-TNF-α treatments resulted in decreased cell viability in both PDAC tumor cells and pancreatic satellite cells in similar dose in vitro. In vivo, anti-TNF-α treatments showed effects in reducing desmoplasia and the tumor promoting inflammatory microenvironment in PDAC. Combination of anti-TNF-α treatments with chemotherapy partly overcame chemoresistance of PDAC tumor cells and prolonged the survival of PDAC mouse model. Conclusions In conclusion, our findings indicated that TNF-α in PDAC can be a prognostic and therapeutic target. Inhibition of TNF-α synergized with chemotherapy in PDAC resulted in better pre-clinical responses via killing tumor cells as well as diminishing desmoplasia and inflammation in PDAC tumor stroma. PMID:27835602

Strategies for Increasing Pancreatic Tumor Immunogenicity

PubMed Central

Johnson, Burles A.; Yarchoan, Mark; Lee, Valerie; Laheru, Daniel A.; Jaffee, Elizabeth M.

2017-01-01

Immunotherapy has changed the standard of care for multiple deadly cancers including lung, head and neck, gastric, and some colorectal cancers. However, single agent immunotherapy has had little effect in pancreatic adenocarcinoma (PDAC). Increasing evidence suggests that the PDAC microenvironment is comprised of an intricate network of signals between immune cells, PDAC cells, and stroma, resulting in an immunosuppressive environment resistant to single agent immunotherapies. In this review, we discuss differences between immunotherapy sensitive cancers and PDAC, the complex interactions between PDAC stroma and suppressive tumor infiltrating cells that facilitate PDAC development and progression, the immunologic targets within these complex networks that are drugable, and data supporting combination drug approaches that modulate multiple PDAC signals, which should lead to improved clinical outcomes. PMID:28373364

Assessment of biophysical tumor response to PDT in pancreatic cancer using localized reflectance spectroscopy

NASA Astrophysics Data System (ADS)

Isabelle, Martin; Klubben, William; He, Ting; Laughney, Ashley M.; Glaser, Adam; Krishnaswamy, Venkataramanan; Hoopes, P. Jack; Hasan, Tayyaba; Pogue, Brian W.

2011-02-01

Biophysical changes such as inflammation and necrosis occur immediately following PDT and may be used to assess the treatment response to PDT treatment in-vivo. This study uses localized reflectance measurements to quantify the scatter changes in tumor tissue occurring in response to verteporfin-based PDT treatment in xenograft pancreas tumors. Nude mice were implanted with subcutaneous AsPC-1 pancreatic tumors cells in matrigel, and allowed to establish solid tumors near 100mm3 volume. The mice were sensitized with 1mg/kg of the active component of verteporfin (benzoporphryin derivative, BPD), one hour before light delivery. The optical irradiation was performed using a 1 cm cylindrical interstitial diffusing tip fiber with 20J of red light (690nm). Tumor tissue was excised progressively and imaged, from 1 day to 4 weeks, after PDT treatment. The tissue sections were stained and analyzed by an expert veterinary pathologist, who provided information on tissue regions of interest. This information was correlated with variations in scattering and absorption parameters elucidated from the spectral images and the degree of necrosis and inflammation involvement was identified. Areas of necrosis and dead cells exhibited the lowest average scatter irradiance signature (3.78 and 4.07 respectively) compared to areas of viable pancreatic tumor cells and areas of inflammation (5.81 and 7.19 respectively). Bilirubin absorbance parameters also showed a lower absorbance value in necrotic tissue and areas of dead cells (0.05 and 0.1 respectively) compared to tissue areas for viable pancreatic tumor cells and areas of inflammation (0.28 and 0.35). These results demonstrate that localized reflectance spectroscopy is an imaging modality that can be used to identify tissue features associated with PDT treatment (e.g. necrosis and inflammation) that can be correlated with histopathologically-reviewed H&E stained slides. Further study of this technique may provide means for automated

Circulating tumor DNA as a liquid biopsy target for detection of pancreatic cancer.

PubMed

Takai, Erina; Yachida, Shinichi

2016-10-14

Most pancreatic cancer patients present with advanced metastatic disease, resulting in extremely poor 5-year survival, mainly because of the lack of a reliable modality for early detection and limited therapeutic options for advanced disease. Therefore, there is a need for minimally-invasive diagnostic tools for detecting pancreatic cancer at an early stage, when curative surgery and also novel therapeutic approaches including precision medicine may be feasible. The "liquid biopsy" addresses these unmet clinical needs based on the concept that simple peripheral blood sampling and detection of circulating tumor DNA (ctDNA) could provide diagnostic information. In this review, we provide an overview of the current status of blood-based tests for diagnosis of pancreatic cancer and the potential utility of ctDNA for precision medicine. We also discuss challenges that remain to be addressed in developing practical ctDNA-based liquid biopsy approaches for early diagnosis of pancreatic cancer.

Isolation of circulating tumor cells in pancreatic cancer patients by immunocytochemical assay.

PubMed

Yang, Jing; Zhou, Ying; Zhao, Bin

2018-01-01

The patients diagnosed with pancreatic cancer have the possibilities of getting the cancer again even after resection. The tumor cells identified from blood can be related to different stages of tumor. In this study, we used an immunoassay to detect circulating tumor cells in blood and bone marrow samples. About 120 patients' blood and bone marrow samples were used in this study along with controls. The presence of tumor cells was evaluated with different stages of cancer classified by UICC. The survival rate at each stages of tumor was also analyzed. The tumor cells were isolated both in blood (29%) and bone marrow samples (25%). The prevalence of tumor cells increased with increase in stages of tumor in blood samples. The survival of the patients considerably related to different stages of tumor but it cannot be taken a parameter alone for the patients' survival. © 2017 Wiley Periodicals, Inc.

Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors

PubMed Central

Hontani, Koji; Tsuchikawa, Takahiro; Hiwasa, Takaki; Nakamura, Toru; Ueno, Takashi; Kushibiki, Toshihiro; Takahashi, Mizuna; Inoko, Kazuho; Takano, Hironobu; Takeuchi, Satoshi; Dosaka-Akita, Hirotoshi; Kuwatani, Masaki; Sakamoto, Naoya; Hatanaka, Yutaka; Mitsuhashi, Tomoko; Shimada, Hideaki; Shichinohe, Toshiaki; Hirano, Satoshi

2017-01-01

Pancreatic neuroendocrine tumors (pNETs) are relatively rare heterogenous tumors, comprising only 1–2% of all pancreatic neoplasms. The majority of pNETs are non-functional tumors (NF-pNETs) that do not produce hormones, and as such, do not cause any hormone-related symptoms. As a result, these tumors are often diagnosed at an advanced stage because patients do not present with specific symptoms. Although tumor markers are used to help diagnosis and predict some types of cancers, chromogranin A, a widely used tumor marker of pNETs, has significant limitations. To identify novel NF-pNET-associated antigens, we performed serological identification of antigens by recombinant cDNA expression cloning (SEREX) and identified five tumor antigens (phosphatase and tensin homolog, EP300-interacting inhibitor of differentiation 3 [EID3], EH domain-containing protein 1, galactoside-binding soluble 9, and BRCA1-associated protein). Further analysis using the AlphaLISA® immunoassay to compare serum antibody levels revealed that antibody levels against the EID3 antigen was significantly higher in the patient group than in the healthy donor group (n = 25, both groups). In addition, higher serum anti-EID3 antibody levels in NF-pNET patients correlated with shorter disease-free survival. The AUC calculated by ROC analysis was 0.784 with moderate diagnostic accuracy. In conclusion, serum anti-EID3 antibody levels may be useful as a tumor marker for prediction of tumor recurrence in NF-pNETs. PMID:29290942

Clinical Value of Dual-energy CT in Detection of Pancreatic Adenocarcinoma: Investigation of the Best Pancreatic Tumor Contrast to Noise Ratio.

PubMed

He, Yong-Lan; Zhang, Da-Ming; Xue, Hua-Dan; Jin, Zheng-Yu

2013-01-01

Objective To quantitatively compare and determine the best pancreatic tumor contrast to noise ratio (CNR) in different dual-energy derived datasets. Methods In this retrospective, single center study, 16 patients (9 male, 7 female, average age 59.4±13.2 years) with pathologically diagnosed pancreatic cancer were enrolled. All patients received an abdominal scan using a dual source CT scanner 7 to 31 days before biopsy or surgery. After injection of iodine contrast agent, arterial and pancreatic parenchyma phase were scanned consequently, using a dual-energy scan mode (100 kVp/230 mAs and Sn 140 kVp/178 mAs) in the pancreatic parenchyma phase. A series of derived dual-energy datasets were evaluated including non-liner blending (non-linear blending width 0-500 HU; blending center -500 to 500 HU), mono-energetic (40-190 keV), 100 kVp and 140 kVp. On each datasets, mean CT values of the pancreatic parenchyma and tumor, as well as standard deviation CT values of subcutaneous fat and psoas muscle were measured. Regions of interest of cutaneous fat and major psoas muscle of 100 kVp and 140 kVp images were calculated. Best CNR of subcutaneous fat (CNRF) and CNR of the major psoas muscle (CNRM) of non-liner blending and mono-energetic datasets were calculated with the optimal mono-energetic keV setting and the optimal blending center/width setting for the best CNR. One Way ANOVA test was used for comparison of best CNR between different dual-energy derived datasets. Results The best CNRF (4.48±1.29) was obtained from the non-liner blending datasets at blending center -16.6±103.9 HU and blending width 12.3±10.6 HU. The best CNRF (3.28±0.97) was obtained from the mono-energetic datasets at 73.3±4.3 keV. CNRF in the 100 kVp and 140 kVp were 3.02±0.91 and 1.56±0.56 respectively. Using fat as the noise background, all of these images series showed significant differences (P<0.01) except best CNRF of mono-energetic image sets vs. CNRF of 100 kVp image (P=0.460). Similar

Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular-fibrosis and tumor progression

PubMed Central

Laklai, Hanane; Miroshnikova, Yekaterina A.; Pickup, Michael W.; Collisson, Eric A.; Kim, Grace E.; Barrett, Alex S.; Hill, Ryan C.; Lakins, Johnathon N.; Schlaepfer, David D.; Mouw, Janna K.; LeBleu, Valerie S.; Roy, Nilotpal; Novitskiy, Sergey V.; Johansen, Julia S.; Poli, Valeria; Kalluri, Raghu; Iacobuzio-Donahue, Christine A.; Wood, Laura D.; Hebrok, Matthias; Hansen, Kirk; Moses, Harold L.; Weaver, Valerie M.

2016-01-01

Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality yet anti-stromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor β (TGF-β) signaling have elevated epithelial Stat3 activity and develop a stiffer, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several Kras-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby Stat3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial Stat3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated Stat3 associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors, and highlight Stat3 and mechanics as key drivers of this phenotype. PMID:27089513

Pancreatic Cancer—Health Professional Version

Cancer.gov

Exocrine pancreatic cancer is cancer of the exocrine gland of the pancreas, whereas cancer of the endocrine gland usually forms as a collection of tumor cell types referred to as pancreatic neuroendocrine tumors. Find evidence-based information on pancreatic cancer treatment, research, and statistics.

Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

PubMed

Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

2016-06-01

The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages

Circulating tumor DNA as a liquid biopsy target for detection of pancreatic cancer

PubMed Central

Takai, Erina; Yachida, Shinichi

2016-01-01

Most pancreatic cancer patients present with advanced metastatic disease, resulting in extremely poor 5-year survival, mainly because of the lack of a reliable modality for early detection and limited therapeutic options for advanced disease. Therefore, there is a need for minimally-invasive diagnostic tools for detecting pancreatic cancer at an early stage, when curative surgery and also novel therapeutic approaches including precision medicine may be feasible. The “liquid biopsy” addresses these unmet clinical needs based on the concept that simple peripheral blood sampling and detection of circulating tumor DNA (ctDNA) could provide diagnostic information. In this review, we provide an overview of the current status of blood-based tests for diagnosis of pancreatic cancer and the potential utility of ctDNA for precision medicine. We also discuss challenges that remain to be addressed in developing practical ctDNA-based liquid biopsy approaches for early diagnosis of pancreatic cancer. PMID:27784960

Management of the Primary Tumor and Limited Metastases in Patients With Metastatic Pancreatic Cancer.

PubMed

Herman, Joseph M; Hoffman, John P; Thayer, Sarah P; Wolff, Robert A

2015-05-01

New combinations of cytotoxic chemotherapy have been proven to increase response rates and survival times compared with single-agent gemcitabine for patients with metastatic pancreatic cancer. These responses have been dramatic for a subset of patients, therefore raising questions about the management of limited metastatic disease with surgery or other ablative methods. Similarly, for patients having a complete radiographic response to chemotherapy in the metastatic compartment, whether to consider local therapy in the form of radiation or surgery for the primary tumor is now an appropriate question. Therefore, collaboration among experts in surgery, medical oncology, and radiation oncology has led to the development of guiding principles for local therapies to the primary intact pancreatic tumor for patients with limited metastatic disease and those who have had a significant response after systemic therapy.

Thermal therapy of pancreatic tumors using endoluminal ultrasound: parametric and patient-specific modeling

PubMed Central

Adams, Matthew S.; Scott, Serena J.; Salgaonkar, Vasant A.; Sommer, Graham; Diederich, Chris J.

2016-01-01

Purpose To investigate endoluminal ultrasound applicator configurations for volumetric thermal ablation and hyperthermia of pancreatic tumors using 3D acoustic and biothermal finite element models. Materials and Methods Parametric studies compared endoluminal heating performance for varying applicator transducer configurations (planar, curvilinear-focused, or radial-diverging), frequencies (1–5 MHz), and anatomical conditions. Patient-specific pancreatic head and body tumor models were used to evaluate feasibility of generating hyperthermia and thermal ablation using an applicator positioned in the duodenal or stomach lumen. Temperature and thermal dose were calculated to define ablation (>240 EM43°C) and moderate hyperthermia (40–45 °C) boundaries, and to assess sparing of sensitive tissues. Proportional-integral control was incorporated to regulate maximum temperature to 70–80 °C for ablation and 45 °C for hyperthermia in target regions. Results Parametric studies indicated that 1–3 MHz planar transducers are most suitable for volumetric ablation, producing 5–8 cm3 lesion volumes for a stationary 5 minute sonication. Curvilinear-focused geometries produce more localized ablation to 20–45 mm depth from the GI tract and enhance thermal sparing (Tmax<42 °C) of the luminal wall. Patient anatomy simulations show feasibility in ablating 60.1–92.9% of head/body tumor volumes (4.3–37.2 cm3) with dose <15 EM43°C in the luminal wall for 18–48 min treatment durations, using 1–3 applicator placements in GI lumen. For hyperthermia, planar and radial-diverging transducers could maintain up to 8 cm3 and 15 cm3 of tissue, respectively, between 40–45 °C for a single applicator placement. Conclusions Modeling studies indicate the feasibility of endoluminal ultrasound for volumetric thermal ablation or hyperthermia treatment of pancreatic tumor tissue. PMID:27097663

A model for cell migration in non-isotropic fibrin networks with an application to pancreatic tumor islets.

PubMed

Chen, Jiao; Weihs, Daphne; Vermolen, Fred J

2018-04-01

Cell migration, known as an orchestrated movement of cells, is crucially important for wound healing, tumor growth, immune response as well as other biomedical processes. This paper presents a cell-based model to describe cell migration in non-isotropic fibrin networks around pancreatic tumor islets. This migration is determined by the mechanical strain energy density as well as cytokines-driven chemotaxis. Cell displacement is modeled by solving a large system of ordinary stochastic differential equations where the stochastic parts result from random walk. The stochastic differential equations are solved by the use of the classical Euler-Maruyama method. In this paper, the influence of anisotropic stromal extracellular matrix in pancreatic tumor islets on T-lymphocytes migration in different immune systems is investigated. As a result, tumor peripheral stromal extracellular matrix impedes the immune response of T-lymphocytes through changing direction of their migration.

Chronic stress accelerates pancreatic cancer growth and invasion: A critical role for beta-adrenergic signaling in the pancreatic microenvironment

PubMed Central

Kim-Fuchs, Corina; Le, Caroline P.; Pimentel, Matthew A.; Shackleford, David; Ferrari, Davide; Angst, Eliane; Hollande, Frédéric; Sloan, Erica K.

2014-01-01

Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of β-adrenergic signaling induced similar effects to chronic stress, and pharmacological β-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural β-adrenergic signaling regulates pancreatic cancer progression and suggest β-blockade as a novel strategy to complement existing therapies for pancreatic cancer. PMID:24650449

TH-CD-207A-04: Optimized Respiratory Gating for Abnormal Breathers in Pancreatic SBRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Campbell, W; Miften, M; Schefter, T

Purpose: Pancreatic SBRT is uniquely challenging due to both the erratic/unstable motion of the pancreas and the close proximity of the radiosensitive small bowel. Respiratory gating can mitigate this effect, but the irregularity of motion severely affects traditional phase-based gating. The purpose of this study was to analyze real-time motion data of pancreatic tumors to optimize the efficacy and accuracy of respiratory gating, with the overall goal of enabling dose escalated pancreatic SBRT. Methods: Fifteen pancreatic SBRT patients received 30–33 Gy in 5 fractions on a Varian TrueBeam STx unit. Abdominal compression was used to reduce the amplitude of tumormore » motion, and daily cone-beam computed tomography (CBCT) scans were acquired prior to each treatment for target localization purposes. For this study, breathing data (phase and amplitude) were collected during each CBCT scan using Varian’s Real-Time Position Management system. An in-house template matching technique was used to track the superior-inferior motion of implanted fiducial markers in CBCT projection images. Using tumor motion and breathing data, phase-based or amplitude-based respiratory gating was simulated for all 75 fractions, targeting either end-exhalation or end-inhalation phases of breathing. Results: For the average patient, gating at end-exhalation offered the best reductions in effective motion for equal duty cycles. However, optimal central phase angle varied widely (range: 0–92%, mean±SD: 49±12%), and phase-based gating windows typically associated with end-exhalation (i.e., “30–70%”) were rarely ideal. Amplitude-based gating significantly outperformed phase-based gating, with average effective ranges for amplitude-based gating 25% lower than phase-based gating ranges (as much as 73% lower). Amplitude-based gating was consistently better suited to accommodate abnormal breathing patterns. For both phase-based and amplitude-based gating, end-exhalation provided

Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids.

PubMed

Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B; Crawford, Howard C; Arrowsmith, Cheryl; Kalloger, Steve E; Renouf, Daniel J; Connor, Ashton A; Cleary, Sean; Schaeffer, David F; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K

2015-11-01

There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids

PubMed Central

Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B.; Crawford, Howard C.; Arrowsmith, Cheryl; Kalloger, Steve E.; Renouf, Daniel J.; Connor, Ashton A; Cleary, Sean; Schaeffer, David F.; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K.

2016-01-01

There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. Culture conditions are also defined for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture, phenotypic heterogeneity of the primary tumor, and retain patient-specific physiologic changes including hypoxia, oxygen consumption, epigenetic marks, and differential sensitivity to EZH2 inhibition. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies. PMID:26501191

Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-β-catenin signaling to slow tumor progression.

PubMed

Froeling, Fieke E M; Feig, Christine; Chelala, Claude; Dobson, Richard; Mein, Charles E; Tuveson, David A; Clevers, Hans; Hart, Ian R; Kocher, Hemant M

2011-10-01

Patients with pancreatic ductal adenocarcinoma are deficient in vitamin A, resulting in activation of pancreatic stellate cells (PSCs). We investigated whether restoration of retinol to PSCs restores their quiescence and affects adjacent cancer cells. PSCs and cancer cell lines (AsPc1 and Capan1) were exposed to doses and isoforms of retinoic acid (RA) in 2-dimensional and 3-dimensional culture conditions (physiomimetic organotypic culture). The effects of all-trans retinoic acid (ATRA) were studied in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice, a model of human pancreatic ductal adenocarcinoma. After incubation with ATRA, PSCs were quiescent and had altered expression of genes that regulate proliferation, morphology, and motility; genes that encode cytoskeletal proteins and cytokines; and genes that control other functions, irrespective of culture conditions or dosage. In the organotypic model, and in mice, ATRA induced quiescence of PSCs and thereby reduced cancer cell proliferation and translocation of β-catenin to the nucleus, increased cancer cell apoptosis, and altered tumor morphology. ATRA reduced the motility of PSCs, so these cells created a "wall" at the junction between the tumor and the matrix that prevented cancer cell invasion. Restoring secreted frizzled-related protein 4 (sFRP4) secretion to quiescent PSCs reduced Wnt-β-catenin signaling in cancer cells and their invasive ability. Human primary and metastatic pancreatic tumor tissues stained strongly for cancer cell nuclear β-catenin but had low levels of sFRP4 (in cancer cells and PSCs). RA induces quiescence and reduces motility of PSCs, leading to reduced proliferation and increased apoptosis of surrounding pancreatic cancer cells. RA isoforms might be developed as therapeutic reagents for pancreatic cancer. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Effect of Audio Coaching on Correlation of Abdominal Displacement With Lung Tumor Motion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakamura, Mitsuhiro; Narita, Yuichiro; Matsuo, Yukinori

2009-10-01

Purpose: To assess the effect of audio coaching on the time-dependent behavior of the correlation between abdominal motion and lung tumor motion and the corresponding lung tumor position mismatches. Methods and Materials: Six patients who had a lung tumor with a motion range >8 mm were enrolled in the present study. Breathing-synchronized fluoroscopy was performed initially without audio coaching, followed by fluoroscopy with recorded audio coaching for multiple days. Two different measurements, anteroposterior abdominal displacement using the real-time positioning management system and superoinferior (SI) lung tumor motion by X-ray fluoroscopy, were performed simultaneously. Their sequential images were recorded using onemore » display system. The lung tumor position was automatically detected with a template matching technique. The relationship between the abdominal and lung tumor motion was analyzed with and without audio coaching. Results: The mean SI tumor displacement was 10.4 mm without audio coaching and increased to 23.0 mm with audio coaching (p < .01). The correlation coefficients ranged from 0.89 to 0.97 with free breathing. Applying audio coaching, the correlation coefficients improved significantly (range, 0.93-0.99; p < .01), and the SI lung tumor position mismatches became larger in 75% of all sessions. Conclusion: Audio coaching served to increase the degree of correlation and make it more reproducible. In addition, the phase shifts between tumor motion and abdominal displacement were improved; however, all patients breathed more deeply, and the SI lung tumor position mismatches became slightly larger with audio coaching than without audio coaching.« less

Loss of Stromal Caveolin-1 Expression: A Novel Tumor Microenvironment Biomarker That Can Predict Poor Clinical Outcomes for Pancreatic Cancer

PubMed Central

Shan, Tao; Lu, Hongwei; Ji, Hong; Li, Yiming; Guo, Jian; Chen, Xi; Wu, Tao

2014-01-01

Aims Cancer development and progression is not only associated with the tumor cell proliferation but also depends on the interaction between tumor cells and the stromal microenvironment. A new understanding of the role of the tumor microenvironment suggests that the loss of stromal caveolin-1 (Cav-1) as a key regulator may become a potential therapy target. This study aims to elucidate whether stromal Cav-1 expression in pancreatic cancer can be a strong prognosis biomarker. Methods Tissue samples from 45 pancreatic cancer patients were studied. Parenchyma and stroma were separated and purified using laser capture microdissection. Stromal Cav-1 expression was measured from pancreatic cancer, paraneoplastic, and normal tissue using immunohistochemistry. We analyzed the correlation of stromal Cav-1 expression with clinicopathologic features and prognostic indicators, such as tumor marker HER-2/neu gene. Results Specimens from six patients (13.3%) showed high levels of stromal Cav-1 staining, those from eight patients (17.8%) showed a lower, intermediate level of staining, whereas those from 31 patients (68.9%) showed an absence of staining. Cav-1 expression in cancer-associated fibroblasts was lower than that in paracancer-associated and in normal fibroblasts. Stromal Cav-1 loss was associated with TNM stage (P = 0.018), lymph node metastasis (P = 0.014), distant metastasis (P = 0.027), and HER-2/neu amplification (P = 0.007). The relationships of age, sex, histological grade, and tumor size with stromal Cav-1 expression were not significant (P>0.05). A negative correlation was found between circulating tumor cells and stromal Cav-1 expression (P<0.05). Conclusion The loss of stromal Cav-1 in pancreatic cancer was an independent prognostic indicator, thus suggesting that stromal Cav-1 may be an effective therapeutic target for patients with pancreatic cancer. PMID:24949874

HDAC gene expression in pancreatic tumor cell lines following treatment with the HDAC inhibitors panobinostat (LBH589) and trichostatine (TSA).

PubMed

Mehdi, Ouaïssi; Françoise, Silvy; Sofia, Costa Lima; Urs, Giger; Kevin, Zemmour; Bernard, Sastre; Igor, Sielezneff; Anabela, Cordeiro-da-Silva; Dominique, Lombardo; Eric, Mas; Ali, Ouaïssi

2012-01-01

In this study, the effect of LBH589 and trichostatin (TSA), a standard histone deacetylase inhibitor (HDACi) toward the growth of pancreatic cancer cell lines was studied. Thus, we examined for the first time, the HDAC family gene expression levels before and after drug treatment. Several human pancreatic cancer cell lines (Panc-1, BxPC-3, SOJ-6) and a normal human pancreatic duct immortalized epithelial cell line (HPDE/E6E7) were used as target cells. The cell growth was measured by MTT assay, cell cycle alteration, membrane phosphatidylserine exposure, DNA fragmentation, mitochondrial membrane potential loss, RT-PCR and Western blots were done using standard methods. The effect of drugs on tumor growth in vivo was studied using subcutaneous xenograft model. Except in the case of certain HDAC gene/tumor cell line couples: (SIRT1/HPDE-SOJ6/TSA- or LBH589-treated cells; LBH589-treated Panc-1 Cells; HDAC2/BxPC-3/LBH589-treated cells or TSA-treated SOJ-6-1 cells), there were no major significant changes of HDACs genes transcription in cells upon drug treatment. However, significant variation in HDACs and SIRTs protein expression levels could be seen among individual cell samples. The in vivo results showed that LBH589 formulation exhibited similar tumor reduction efficacy as the commercial drug gemcitabine. Our data demonstrate that LBH589 induced the death of pancreatic tumor cell by apoptosis. In line with its in vitro activity, LBH589 achieved a significant reduction in tumor growth in BxPC-3 pancreatic tumor cell line subcutaneous xenograft mouse model. Furthermore, exploring the impact of LBH589 on HDACs encoding genes expression revealed for the first time that some of them, depending on the cell line considered, seem to be regulated during translation. Copyright © 2012 IAP and EPC. Published by Elsevier B.V. All rights reserved.

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

PubMed Central

Duewell, P; Steger, A; Lohr, H; Bourhis, H; Hoelz, H; Kirchleitner, S V; Stieg, M R; Grassmann, S; Kobold, S; Siveke, J T; Endres, S; Schnurr, M

2014-01-01

Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor-derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8α+ DCs effectively engulfed apoptotic tumor material and cross-presented tumor-associated antigen to naive CD8+ T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity. PMID:25012502

Current immunotherapeutic strategies in pancreatic cancer.

PubMed

Plate, Janet M D

2007-10-01

The immune systems of patients with newly diagnosed pancreatic cancers are functional, with T-cell responses capable of responding to tumor antigen presentation. Pancreatic tumors have been demonstrated to express tumor antigens as mutated, altered, underglycosylated and/or inappropriately overexpressed proteins. Considering these two facts, it should be possible for patients' bodies to recognize their tumors as foreign and to reject them. A number of clinical trials have been initiated to exploit this immune activation to eradicate or stabilize tumor growth. Immunotherapeutic trials include the specific testing of a variety of tumor vaccines, of cytokines as adjuvants or directed cytotoxicity, and of monoclonal antibodies to target specific molecules. This article reviews evidence for immune-cell activation and function in patients with pancreatic cancer, and evidence that pancreatic tumor cells express tumor antigens, or mutated (or altered) proteins. Nevertheless, tumors survive immune attacks by producing products that help them to circumvent effector T cells. The article thus examines complications of immune evasion by cancer cells, as well as the challenges of trying to exploit the immune system in solid tumors where tumor cell products can turn off invading immune T cells set to kill them. Finally, the article discusses the choices of a variety of clinical trials using immune modulation for patients with pancreatic cancer.

A Case of a Composite Adrenal Medullary Tumor of Pheochromocytoma and Ganglioneuroma Masquerading as Acute Pancreatitis

PubMed Central

Choi, Eun-Kyoung; Kim, Wan-Ho

2006-01-01

Composite adrenal medullary tumors, composed of both pheochromocytoma and ganglioneuroma, are extremely rare, as are pheochromocytomas masquerading as acute relapsing pancreatitis. We recently experienced a case of a 48-year-old male with both these phenomena. The patient complained of an acute onset of intense abdominal discomfort. At the same time, pancreatic enzymes were increased in concentration. An abdominal computed tomographic scan revealed an enlarged pancreas and a 3-cm left adrenal incidentaloma. Biochemical and 131I-MIBG scintigraphic findings were compatible with a pheochromocytoma. Yet, he had no clinical manifestations suggesting pheochromocytoma. An adrenalectomy was performed and a composite adrenal medullary tumor of pheochromocytoma and ganglioneuroma was confirmed during a pathologic examination. This case illustrates two points: 1) acute abdominal intense discomfort and hyperamylasemia may be unusual presentations of pheochromocytomas; and 2) the possibility of the pheochromocytoma, albeit rare, should be considered when a relapsing pancreatitis of uncertain etiology develops. PMID:16913447

Short- and long-term outcomes after enucleation of pancreatic tumors: An evidence-based assessment.

PubMed

Zhou, Yanming; Zhao, Min; Wu, Lupeng; Ye, Feng; Si, Xiaoying

Enucleation of pancreatic tumors is rarely performed. The aim of this study was to evaluate the published evidence for its short- and long-term outcomes. PubMed (MEDLINE) and EMBASE databases were searched from 1990 to March 2016. Studies including at least ten patients who underwent enucleation of pancreatic lesions were included. Data on the outcomes were synthesized and meta-analyzed where appropriate. Twenty-seven studies involving 1316 patients were included in the systematic review. The postoperative mortality was 0.3%, and the postoperative morbidity was 50.3%, mainly represented by pancreatic fistula (38.1%). Endocrine insufficiency, exocrine insufficiency and tumor recurrence was observed in 2.4%, 1.1% and 2.3% of the patients respectively. Compared with typical resection, the operation time, blood loss, length of hospital stay, and the incidence of endocrine and exocrine insufficiency were all significantly reduced after enucleation. The occurrence of pancreatic fistula was significantly higher in enucleation group, but overall morbidity, the reoperation rate and mortality were comparable between the two groups. There was no significant difference in disease recurrence between the two groups. Compared with central pancreatectomy, enucleation had a shorter operation time, lower blood loss, less morbidity, and better pancreatic function. Compared with open enucleation, minimally invasive enucleation had a shorter operation time and a shorter length of hospital stay. Enucleation is an appropriate surgical procedure in selected patients with benign or low-malignant lesions of the pancreas. The benefits of minimally invasive approach need to be validated in further investigations with larger groups of patients. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Zyflamend Suppresses Growth and Sensitizes Human Pancreatic Tumors to Gemcitabine in an Orthotopic Mouse Model Through Modulation of Multiple Targets

PubMed Central

Kunnumakkara, Ajaikumar B.; Sung, Bokyung; Ravindran, Jayaraj; Diagaradjane, Parmeswaran; Deorukhkar, Amit; Dey, Sanjit; Koca, Cemile; Tong, Zhimin; Gelovani, Juri G.; Guha, Sushovan; Krishnan, Sunil; Aggarwal, Bharat B.

2011-01-01

Agents that can potentiate the efficacy of standard chemotherapy against pancreatic cancer are of great interest. Because of their low cost and safety, patients commonly use a variety of dietary supplements, although evidence of their efficacy is often lacking. One such commonly used food supplement, Zyflamend, is a polyherbal preparation with potent anti-inflammatory activities, and preclinical efficacy against prostate and oral cancer. Whether Zyflamend has any efficacy against human pancreatic cancer alone or in combination with gemcitibine, a commonly used agent, was examined in cell cultures and in an orthotopic mouse model. In vitro, Zyflamend inhibited the proliferation of pancreatic cancer cell lines regardless of p53 status and also enhanced gemcitabine-induced apoptosis. This finding correlated with inhibition of NF-κB activation by Zyflamend and suppression of cyclin D1, c-myc, COX-2, Bcl-2, IAP, survivin, VEGF, ICAM-1, and CXCR4. In nude mice, oral administration of Zyflamend alone significantly inhibited the growth of orthotopically transplanted human pancreatic tumors, and when combined with gemcitabine, further enhanced the antitumor effects. Immunohistochemical and Western blot analyses of tumor tissue showed that the suppression of pancreatic cancer growth correlated with inhibition of proliferation index marker (Ki-67), COX-2, MMP-9, NF-κB, and VEGF. Overall, these results suggest that the concentrated multiherb product Zyflamend alone can inhibit the growth of human pancreatic tumors and, in addition, can sensitize pancreatic cancers to gemcitabine through the suppression of multiple targets linked to tumorigenesis. PMID:21935918

A practical approach to pancreatic cancer immunotherapy using resected tumor lysate vaccines processed to express α-gal epitopes

PubMed Central

Miyoshi, Eiji; Eguchi, Hidetoshi; Nagano, Hiroaki; Matsunami, Katsuyoshi; Nagaoka, Satoshi; Yamada, Daisaku; Asaoka, Tadafumi; Noda, Takehiro; Wada, Hiroshi; Kawamoto, Koichi; Goto, Kunihito; Taniyama, Kiyomi; Mori, Masaki; Doki, Yuichiro

2017-01-01

Objectives Single-agent immunotherapy is ineffective against poorly immunogenic cancers, including pancreatic ductal adenocarcinoma (PDAC). The aims of this study were to demonstrate the feasibility of production of novel autologous tumor lysate vaccines from resected PDAC tumors, and verify vaccine safety and efficacy. Methods Fresh surgically resected tumors obtained from human patients were processed to enzymatically synthesize α-gal epitopes on the carbohydrate chains of membrane glycoproteins. Processed membranes were analyzed for the expression of α-gal epitopes and the binding of anti-Gal, and vaccine efficacy was assessed in vitro and in vivo. Results Effective synthesis of α-gal epitopes was demonstrated after processing of PDAC tumor lysates from 10 different patients, and tumor lysates readily bound an anti-Gal monoclonal antibody. α-gal(+) PDAC tumor lysate vaccines elicited strong antibody production against multiple tumor-associated antigens and activated multiple tumor-specific T cells. The lysate vaccines stimulated a robust immune response in animal models, resulting in tumor suppression and a significant improvement in survival without any adverse events. Conclusions Our data suggest that α-gal(+) PDAC tumor lysate vaccination may be a practical and effective new immunotherapeutic approach for treating pancreatic cancer. PMID:29077749

A practical approach to pancreatic cancer immunotherapy using resected tumor lysate vaccines processed to express α-gal epitopes.

PubMed

Furukawa, Kenta; Tanemura, Masahiro; Miyoshi, Eiji; Eguchi, Hidetoshi; Nagano, Hiroaki; Matsunami, Katsuyoshi; Nagaoka, Satoshi; Yamada, Daisaku; Asaoka, Tadafumi; Noda, Takehiro; Wada, Hiroshi; Kawamoto, Koichi; Goto, Kunihito; Taniyama, Kiyomi; Mori, Masaki; Doki, Yuichiro

2017-01-01

Single-agent immunotherapy is ineffective against poorly immunogenic cancers, including pancreatic ductal adenocarcinoma (PDAC). The aims of this study were to demonstrate the feasibility of production of novel autologous tumor lysate vaccines from resected PDAC tumors, and verify vaccine safety and efficacy. Fresh surgically resected tumors obtained from human patients were processed to enzymatically synthesize α-gal epitopes on the carbohydrate chains of membrane glycoproteins. Processed membranes were analyzed for the expression of α-gal epitopes and the binding of anti-Gal, and vaccine efficacy was assessed in vitro and in vivo. Effective synthesis of α-gal epitopes was demonstrated after processing of PDAC tumor lysates from 10 different patients, and tumor lysates readily bound an anti-Gal monoclonal antibody. α-gal(+) PDAC tumor lysate vaccines elicited strong antibody production against multiple tumor-associated antigens and activated multiple tumor-specific T cells. The lysate vaccines stimulated a robust immune response in animal models, resulting in tumor suppression and a significant improvement in survival without any adverse events. Our data suggest that α-gal(+) PDAC tumor lysate vaccination may be a practical and effective new immunotherapeutic approach for treating pancreatic cancer.

Immune cell functions in pancreatic cancer.

PubMed

Plate, J M; Harris, J E

2000-01-01

Pancreatic cancer kills nearly 29,000 people in the United States annually-as many people as are diagnosed with the disease. Chemotherapeutic treatment is ineffective in halting progression of the disease. Yet, specific immunity to pancreatic tumor cells in subjects with pancreatic cancer has been demonstrated repeatedly during the last 24 years. Attempts to expand and enhance tumor-specific immunity with biotherapy, however, have not met with success. The question remains, "Why can't specific immunity regulate pancreatic cancer growth?" The idea that tumor cells have evolved protective mechanisms against immunity was raised years ago and has recently been revisited by a number of research laboratories. In pancreatic cancer, soluble factors produced by and for the protection of the tumor environment have been detected and are often distributed to the victim's circulatory system where they may effect a more generalized immunosuppression. Yet the nature of these soluble factors remains controversial, since some also serve as tumor antigens that are recognized by the same T cells that may become inactivated by them. Unless the problem of tumor-derived immunosuppressive products is addressed directly through basic and translational research studies, successful biotherapeutic treatment for pancreatic cancer may not be forthcoming.

Simulation of dosimetric consequences of 4D-CT-based motion margin estimation for proton radiotherapy using patient tumor motion data

NASA Astrophysics Data System (ADS)

Koybasi, Ozhan; Mishra, Pankaj; St. James, Sara; Lewis, John H.; Seco, Joao

2014-02-01

For the radiation treatment of lung cancer patients, four-dimensional computed tomography (4D-CT) is a common practice used clinically to image tumor motion and subsequently determine the internal target volume (ITV) from the maximum intensity projection (MIP) images. ITV, which is derived from short pre-treatment 4D-CT scan (<6 s per couch position), may not adequately cover the extent of tumor motion during the treatment, particularly for patients that exhibit a large respiratory variability. Inaccurate tumor localization may result in under-dosage of the tumor or over-dosage of the surrounding tissues. The purpose of this study is therefore to assess the degree of tumor under-dosage in case of regular and irregular breathing for proton radiotherapy using ITV-based treatment planning. We place a spherical lesion into a modified XCAT phantom that is also capable of producing 4D images based on irregular breathing, and move the tumor according to real tumor motion data, which is acquired over multiple days by tracking gold fiducial markers implanted into the lung tumors of patients. We derive ITVs by taking the union of all tumor positions during 6 s of tumor motion in the phantom using the first day patient tumor tracking data. This is equivalent to ITVs generated clinically from cine-mode 4D-CT MIP images. The treatment plans created for different ITVs are then implemented on dynamic phantoms with tumor motion governed by real tumor tracking data from consecutive days. By comparing gross tumor volume dose distribution on days of ‘treatment’ with the ITV dose distribution, we evaluate the deviation of the actually delivered dose from the predicted dose. Our results have shown that the proton treatment planning on ITV derived from pre-treatment cine-mode 4D-CT can result in under-dosage (dose covering 95% of volume) of the tumor by up to 25.7% over 3 min of treatment for the patient with irregular respiratory motion. Tumor under-dosage is less significant for

Development of a novel preclinical pancreatic cancer research model: bioluminescence image-guided focal irradiation and tumor monitoring of orthotopic xenografts.

PubMed

Tuli, Richard; Surmak, Andrew; Reyes, Juvenal; Hacker-Prietz, Amy; Armour, Michael; Leubner, Ashley; Blackford, Amanda; Tryggestad, Erik; Jaffee, Elizabeth M; Wong, John; Deweese, Theodore L; Herman, Joseph M

2012-04-01

We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. Luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. BLI was correlated to positron emission tomography (PET)/computed tomography (CT) to estimate tumor dimensions. BLI and cone-beam CT (CBCT) were used to compare tumor centroid location and estimate setup error. BLI and CBCT fusion was performed to guide irradiation of tumors using the small animal radiation research platform (SARRP). DNA damage was assessed by γ-H2Ax staining. BLI was used to longitudinally monitor treatment response. Bioluminescence predicted tumor volume (R = 0.8984) and increased linearly as a function of time up to a 10-fold increase in tumor burden. BLI correlated with PET/CT and necropsy specimen in size (P < .05). Two-dimensional BLI centroid accuracy was 3.5 mm relative to CBCT. BLI-guided irradiated pancreatic tumors stained positively for γ-H2Ax, whereas surrounding normal tissues were spared. Longitudinal assessment of irradiated tumors with BLI revealed significant tumor growth delay of 20 days relative to controls. We have successfully applied the SARRP to a bioluminescent, orthotopic preclinical pancreas cancer model to noninvasively: 1) allow the identification of tumor burden before therapy, 2) facilitate image-guided focal radiation therapy, and 3) allow normalization of tumor burden and longitudinal assessment of treatment response.

“Stealth dissemination” of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma

USDA-ARS?s Scientific Manuscript database

Circulating tumor cells (CTCs) appear to be involved in early dissemination of many cancers, although which characteristics are important in metastatic spread are not clear. Here we describe isolation and characterization of macrophage-tumor cell fusions (MTFs) from the blood of pancreatic ductal a...

Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer

PubMed Central

Kang, Rui; Xie, Yangchun; Zhang, Qiuhong; Hou, Wen; Jiang, Qingping; Zhu, Shan; Liu, Jinbao; Zeng, Dexing; Wang, Haichao; Bartlett, David L; Billiar, Timothy R; Zeh, Herbert J; Lotze, Michael T; Tang, Daolin

2017-01-01

Pancreatic ductal adenocarcinoma (PDAC) driven by oncogenic K-Ras remains among the most lethal human cancers despite recent advances in modern medicine. The pathogenesis of PDAC is partly attributable to intrinsic chromosome instability and extrinsic inflammation activation. However, the molecular link between these two events in pancreatic tumorigenesis has not yet been fully established. Here, we show that intracellular high mobility group box 1 (HMGB1) remarkably suppresses oncogenic K-Ras-driven pancreatic tumorigenesis by inhibiting chromosome instability-mediated pro-inflammatory nucleosome release. Conditional genetic ablation of either single or both alleles of HMGB1 in the pancreas renders mice extremely sensitive to oncogenic K-Ras-driven initiation of precursor lesions at birth, including pancreatic intraepithelial neoplasms, intraductal papillary mucinous neoplasms, and mucinous cystic neoplasms. Loss of HMGB1 in the pancreas is associated with oxidative DNA damage and chromosomal instability characterized by chromosome rearrangements and telomere abnormalities. These lead to inflammatory nucleosome release and propagate K-Ras-driven pancreatic tumorigenesis. Extracellular nucleosomes promote interleukin 6 (IL-6) secretion by infiltrating macrophages/neutrophils and enhance oncogenic K-Ras signaling activation in pancreatic lesions. Neutralizing antibodies to IL-6 or histone H3 or knockout of the receptor for advanced glycation end products all limit K-Ras signaling activation, prevent cancer development and metastasis/invasion, and prolong animal survival in Pdx1-Cre;K-RasG12D/+;Hmgb1−/− mice. Pharmacological inhibition of HMGB1 loss by glycyrrhizin limits oncogenic K-Ras-driven tumorigenesis in mice under inflammatory conditions. Diminished nuclear and total cellular expression of HMGB1 in PDAC patients correlates with poor overall survival, supporting intracellular HMGB1 as a novel tumor suppressor with prognostic and therapeutic relevance in

A Novel Deletion Mutation in the MEN1 Gene in a Patient with Prolactinoma and a Family History of Pancreatic Tumors.

PubMed

Kageyama, Kazunori; Usui, Takeshi; Yoshizawa, Kaori; Daimon, Makoto

2014-09-01

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome caused by mutations in the MEN1 gene. Mutations in this tumor suppressor gene are often associated with neuroendocrine tumors. Here we describe a novel deletion mutation at codon 304 in the MEN1 gene of a patient with a prolactinoma and strong family history of pancreatic tumors. We describe the patient's clinical course and mutational analysis and review the relevant literature. A 30-year-old pregnant female was referred to our institution's psychological department for treatment of depression. She had developed a prolactinoma at age 17 and was being treated with 1 mg/week of cabergoline. A medical interview revealed a family history of pancreatic islet cell and other tumors; her mother died of pancreatic cancer, her brother is living with gastrinoma, and her sister died of leiomyosarcoma. Extensive examinations performed after delivery, including laboratory tests and computed tomography (CT) scans, did not reveal any other tumors. Mutational analysis of the MEN1 gene identified a heterozygous deletion mutation (c911_914delAGGT) at codon 304. This mutation produces a frameshift at p.304Lys and might disturb the splicing of intron 6 due to the lack of a donor site. The predicted menin protein from the mutated allele is truncated at amino acid 328. We report a novel deletion mutation (c911_914delAGGT) in the MEN1 gene that was likely associated with the patient's prolactinoma and her strong family history of pancreatic tumors.

SU-G-JeP1-06: Correlation of Lung Tumor Motion with Tumor Location Using Electromagnetic Tracking

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muccigrosso, D; Maughan, N; Parikh, P

Purpose: It is well known that lung tumors move with respiration. However, most measurements of lung tumor motion have studied long treatment times with intermittent imaging; those populations may not necessarily represent conventional LINAC patients. We summarized the correlation between tumor motion and location in a multi-institutional trial with electromagnetic tracking, and identified the patient cohort that would most benefit from respiratory gating. Methods: Continuous electromagnetic transponder data (Varian Medical, Seattle, WA) of lung tumor motion was collected from 14 patients (214 total fractions) across 3 institutions during external beam radiation therapy in a prospective clinical trial (NCT01396551). External interventionmore » from the clinician, such as couch shifts, instructed breath-holds, and acquisition pauses, were manually removed from the 10 Hz tracking data according to recorded notes. The average three-dimensional displacement from the breathing cycle’s end-expiratory to end-inhalation phases (peak-to-peak distance) of the transponders’ isocenter was calculated for each patient’s treatment. A weighted average of each isocenter was used to assess the effects of location on motion. A total of 14 patients were included in this analysis, grouped by their transponders’ location in the lung: upper, medial, and lower. Results: 8 patients had transponders in the upper lung, and 3 patients each in the medial lobe and lower lung. The weighted average ± standard deviation of all peak-to-peak distances for each group was: 1.04 ± 0.39 cm in the lower lung, 0.56 ± 0.14 cm in the medial lung, and 0.30 ± 0.06 cm in the upper lung. Conclusion: Tumors in the lower lung are most susceptible to excessive motion and daily variation, and would benefit most from continuous motion tracking and gating. Those in the medial lobe might be at moderate risk. The upper lobes have limited motion. These results can guide different motion management

Hypoxia Responsive, Tumor Penetrating Lipid Nanoparticles for Delivery of Chemotherapeutics to Pancreatic Cancer Cell Spheroids.

PubMed

Kulkarni, Prajakta; Haldar, Manas K; Katti, Preeya; Dawes, Courtney; You, Seungyong; Choi, Yongki; Mallik, Sanku

2016-08-17

Solid tumors are often poorly irrigated due to structurally compromised microcirculation. Uncontrolled multiplication of cancer cells, insufficient blood flow, and the lack of enough oxygen and nutrients lead to the development of hypoxic regions in the tumor tissues. As the partial pressure of oxygen drops below the necessary level (10 psi), the cancer cells modulate their genetic makeup to survive. Hypoxia triggers tumor progression by enhancing angiogenesis, cancer stem cell production, remodeling of the extracellular matrix, and epigenetic changes in the cancer cells. However, the hypoxic regions are usually located deep in the tumors and are usually inaccessible to the intravenously injected drug carrier or the drug. Considering the designs of the reported nanoparticles, it is likely that the drug is delivered to the peripheral tumor tissues, close to the blood vessels. In this study, we prepared lipid nanoparticles (LNs) comprising the synthesized hypoxia-responsive lipid and a peptide-lipid conjugate. We observed that the resultant LNs penetrated to the hypoxic regions of the tumors. Under low oxygen partial pressure, the hypoxia-responsive lipid undergoes reduction, destabilizing the lipid membrane, and releasing encapsulated drugs from the nanoparticles. We demonstrated the results employing spheroidal cultures of the pancreatic cancer cells BxPC-3. We observed that the peptide-decorated, drug encapsulated LNs reduced the viability of pancreatic cancer cells of the spheroids to 35% under hypoxic conditions.

Pancreatic neuroendocrine tumors: the basics, the gray zone, and the target.

PubMed

Kelgiorgi, Dionysia; Dervenis, Christos

2017-01-01

Pancreatic neuroendocrine tumors (PanNETs) manifest with a range of symptoms and pose a therapeutic challenge. A team approach, in which many specialists come together, is necessary in the quest for the best patient-tailored treatment. Disciplines such as oncology, surgery, basic science, endocrinology, radiology, and nuclear medicine need to work side by side, equally contributing to patient care and to advancing our better understanding of this fascinating disease.

Real-time tumor motion estimation using respiratory surrogate via memory-based learning

NASA Astrophysics Data System (ADS)

Li, Ruijiang; Lewis, John H.; Berbeco, Ross I.; Xing, Lei

2012-08-01

Respiratory tumor motion is a major challenge in radiation therapy for thoracic and abdominal cancers. Effective motion management requires an accurate knowledge of the real-time tumor motion. External respiration monitoring devices (optical, etc) provide a noninvasive, non-ionizing, low-cost and practical approach to obtain the respiratory signal. Due to the highly complex and nonlinear relations between tumor and surrogate motion, its ultimate success hinges on the ability to accurately infer the tumor motion from respiratory surrogates. Given their widespread use in the clinic, such a method is critically needed. We propose to use a powerful memory-based learning method to find the complex relations between tumor motion and respiratory surrogates. The method first stores the training data in memory and then finds relevant data to answer a particular query. Nearby data points are assigned high relevance (or weights) and conversely distant data are assigned low relevance. By fitting relatively simple models to local patches instead of fitting one single global model, it is able to capture highly nonlinear and complex relations between the internal tumor motion and external surrogates accurately. Due to the local nature of weighting functions, the method is inherently robust to outliers in the training data. Moreover, both training and adapting to new data are performed almost instantaneously with memory-based learning, making it suitable for dynamically following variable internal/external relations. We evaluated the method using respiratory motion data from 11 patients. The data set consists of simultaneous measurement of 3D tumor motion and 1D abdominal surface (used as the surrogate signal in this study). There are a total of 171 respiratory traces, with an average peak-to-peak amplitude of ∼15 mm and average duration of ∼115 s per trace. Given only 5 s (roughly one breath) pretreatment training data, the method achieved an average 3D error of 1.5 mm and 95

The Somatostatin Analog Rhenium Re-188-P2045 Inhibits the Growth of AR42J Pancreatic Tumor-xenografts

PubMed Central

Nelson, Carol A.; Azure, Michael T.; Adams, Christopher T.; Zinn, Kurt R.

2015-01-01

P2045 is a peptide analog of somatostatin with picomolar affinity for the somatostatin receptor subtype 2 (SSTR2) upregulated in some pancreatic tumors. Studies were conducted in rat AR42J pancreatic tumor-xenograft mice to determine if Re-188-P2045 could inhibit the growth of pancreatic cancer in an animal model. Methods Re-188-P2045 was intravenously administered every 3 days for 16 days to nude mice with AR42J tumor-xenografts that were ≈ 20 mm3 at study initiation. Tumor volumes were recorded throughout the dosing period. At necropsy all tissues were assessed for levels of radioactivity and evaluated for histological abnormalities. Clinical chemistry and hematology parameters were determined from terminal blood samples. The affinity of non-radioactive Re-185/187-P2045 for somatostatin receptors was compared in human NCI-H69 and rat AR42J tumor-cell membranes expressing predominantly SSTR2. Results In the 1.85 and 5.55 mBq groups tumor growth was inhibited in a dose-dependent fashion. In the 11.1 mBq group tumor growth was completely inhibited throughout the dosing period and for 12 days after the last administered dose. The radioactivity level in tumors 4 hours post-injection was 10%ID/g, which was 2-fold higher than in the kidneys. Re-188-P2045 was well tolerated in all dose-groups with no adverse clinical, histological, or hematological findings. The non-radioactive Re-185/187-P2045 bound more avidly (0.2 nM) to SSTR2 in human than rat tumor membranes suggesting that these studies are relevant to human studies. Conclusion Re-188-P2045 is a promising therapeutic candidate for patients with somatostatin-receptor-positive cancer. PMID:25359879

CDDO-Me inhibits tumor growth and prevents recurrence of pancreatic ductal adenocarcinoma.

PubMed

Gao, Xiaohua; Deeb, Dorrah; Liu, Yongbo; Liu, Patricia; Zhang, Yiguan; Shaw, Jiajiu; Gautam, Subhash C

2015-12-01

Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) has shown potent antitumorigenic activity against a wide range of cancer cell lines in vitro and inhibited the growth of liver, lung and prostate cancer in vivo. In the present study, we examined the antitumor activity of CDDO-Me for pancreatic ductal adenocarcinoma (PDAC) cells with and without activating K-ras mutations. Treatment of K-ras mutant MiaPaCa-2 and K-ras normal BxPC-3 cells with CDDO-Me elicited strong antiproliferative and proapoptopic responses in both cell lines in culture. The inhibition of cell proliferation and induction of apoptosis was accompanied by the inhibition of antiapoptotic/prosurvival p-Akt, NF-кB and p-mTOR signaling proteins. For testing efficacy of CDDO-Me in vivo heterotopic and orthotopic xenografts were generated by implanting BxPC-3 and MiaPaCa-2 cells subcutaneously and in the pancreatic tail, respectively. Treatment with CDDO-Me significantly inhibited the growth of BxPC-3 xenografts and reduced the levels of p-Akt and p-mTOR in tumor tissue. In mice with orthotopic MiaPaCa-2 xenografts, treatment with CDDO-Me prolonged the survival of mice when administered following the surgical resection of tumors. The latter was attributed to the eradication of residual PDAC remaining after resection of tumors. These preclinical data demonstrate the potential of CDDO-Me for treating primary PDAC tumors and for preventing relapse/recurrence through the destruction of residual disease.

Pancreatic carcinogenesis: apoptosis and angiogenesis.

PubMed

Onizuka, Shinya; Kawakami, Shunsuke; Taniguchi, Ken; Fujioka, Hikaru; Miyashita, Kosei

2004-04-01

Apoptosis and angiogenesis are critical biologic processes that are altered during carcinogenesis. Both apoptosis and angiogenesis may play an important role in pancreatic carcinogenesis. Despite numerous advances in the diagnosis and treatment of pancreatic cancer, its prognosis remains dismal and a new therapeutic approach is much needed. Recent research has revealed that apoptosis and angiogenesis are closely interrelated. Several reports show that a tumor suppresser gene that is expressed in pancreatic carcinoma and related to malignant potential can induce apoptosis and also inhibit angiogenesis. At present, it is generally accepted that tumor growth in cancers, including pancreatic cancer, depends on angiogenesis. We have identified 2 new angiogenesis inhibitors from a conditioned medium of human pancreatic carcinoma cell line (BxPC-3): antiangiogenic antithrombin III (aaAT-III) and vitamin D binding protein-macrophage activating factor (DBP-maf). These molecules were able to regress tumors in severe combined immunodeficiency disease (SCID) mice, demonstrating potent inhibition of endothelial cell proliferation. Moreover, the angiogenesis inhibitors induced tumor dormancy in the animal model. These results suggest that antiangiogenic therapy using angiogenesis inhibitors may become a new strategy for treatment of pancreatic cancer in the near future.

Pancreatic ductal adenocarcinoma mice lacking mucin 1 have a profound defect in tumor growth and metastasis.

PubMed

Besmer, Dahlia M; Curry, Jennifer M; Roy, Lopamudra D; Tinder, Teresa L; Sahraei, Mahnaz; Schettini, Jorge; Hwang, Sun-Il; Lee, Yong Y; Gendler, Sandra J; Mukherjee, Pinku

2011-07-01

MUC1 is overexpressed and aberrantly glycosylated in more than 60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In this study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared with both KC and KCM. Cell lines derived from KCKO tumors have significantly less tumorigenic capacity compared with cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared with mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor, platelet-derived growth factor, or matrix metalloproteinase 9. Further, significantly less KCKO cells entered the G(2)-M phase of the cell cycle compared with the KCM cells. Proteomics and Western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of mitogen-activated protein kinase (MAPK), as well as a significant decrease in nestin and tubulin-α2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. ©2011 AACR

SU-E-J-133: Evaluation of Inter- and Intra-Fractional Pancreas Tumor Residual Motions with Abdominal Compression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Y; Shi, F; Tian, Z

2014-06-01

Purpose: Abdominal compression (AC) has been widely used to reduce pancreas motion due to respiration for pancreatic cancer patients undergoing stereotactic body radiotherapy (SBRT). However, the inter-fractional and intra-fractional patient motions may degrade the treatment. The purpose of this work is to study daily CBCT projections and 4DCT to evaluate the inter-fractional and intra-fractional pancreatic motions. Methods: As a standard of care at our institution, 4D CT scan was performed for treatment planning. At least two CBCT scans were performed for daily treatment. Retrospective studies were performed on patients with implanted internal fiducial markers or surgical clips. The initial motionmore » pattern was obtained by extracting marker positions on every phase of 4D CT images. Daily motions were presented by marker positions on CBCT scan projection images. An adaptive threshold segmentation algorithm was used to extract maker positions. Both marker average positions and motion ranges were compared among three sets of scans, 4D CT, positioning CBCT, and conformal CBCT, for inter-fractional and intra-fractional motion variations. Results: Data from four pancreatic cancer patients were analyzed. These patients had three fiducial markers implanted. All patients were treated by an Elekta Synergy with single fraction SBRT. CBCT projections were acquired by XVI. Markers were successfully detected on most of the projection images. The inter-fractional changes were determined by 4D CT and the first CBCT while the intra-fractional changes were determined by multiple CBCT scans. It is found that the average motion range variations are within 2 mm, however, the average marker positions may drift by 6.5 mm. Conclusion: The patients respiratory motion variation for pancreas SBRT with AC was evaluated by detecting markers from CBCT projections and 4DCT, both the inter-fraction and intra-fraction motion range change is small but the drift of marker positions may be

Screening for Pancreatic Cancer

PubMed Central

Brand, Randall E.

2007-01-01

Despite improvements in the clinical and surgical management of pancreatic cancer, limited strides have been made in the early detection of this highly lethal malignancy. The majority of localized pancreatic tumors are asymptomatic, and the recognized presenting symptoms of pancreatic adenocarcinoma are often vague and heterogeneous in nature. These factors, coupled with the lack of a sensitive and noninvasive screening method, have made population-based screening for pancreatic cancer impossible. Nevertheless, at least two large institutions have performed multimodality-screening protocols for individuals with high risk of pancreatic cancer based on genetic predisposition and strong family history. Abnormalities noted during these screening protocols prompted further investigation or surgery that resulted in the discovery of benign, potentially malignant, and malignant pancreatic lesions. In addition to ductal epithelial pancreatic intraepithelial neoplasia, greater sensitivity has recently been achieved in the identification and characterization of precancerous mucinous pancreatic tumors. Advancements in proteomics and DNA microarray technology may confirm serum-based biomarkers that could be incorporated into future screening algorithms for pancreatic cancer. PMID:21960811

Four-Dimensional Magnetic Resonance Imaging With 3-Dimensional Radial Sampling and Self-Gating–Based K-Space Sorting: Early Clinical Experience on Pancreatic Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Wensha, E-mail: wensha.yang@cshs.org; Fan, Zhaoyang; Tuli, Richard

2015-12-01

Purpose: To apply a novel self-gating k-space sorted 4-dimensional MRI (SG-KS-4D-MRI) method to overcome limitations due to anisotropic resolution and rebinning artifacts and to monitor pancreatic tumor motion. Methods and Materials: Ten patients were imaged using 4D-CT, cine 2-dimensional MRI (2D-MRI), and the SG-KS-4D-MRI, which is a spoiled gradient recalled echo sequence with 3-dimensional radial-sampling k-space projections and 1-dimensional projection-based self-gating. Tumor volumes were defined on all phases in both 4D-MRI and 4D-CT and then compared. Results: An isotropic resolution of 1.56 mm was achieved in the SG-KS-4D-MRI images, which showed superior soft-tissue contrast to 4D-CT and appeared to be free of stitchingmore » artifacts. The tumor motion trajectory cross-correlations (mean ± SD) between SG-KS-4D-MRI and cine 2D-MRI in superior–inferior, anterior–posterior, and medial–lateral directions were 0.93 ± 0.03, 0.83 ± 0.10, and 0.74 ± 0.18, respectively. The tumor motion trajectories cross-correlations between SG-KS-4D-MRI and 4D-CT in superior–inferior, anterior–posterior, and medial–lateral directions were 0.91 ± 0.06, 0.72 ± 0.16, and 0.44 ± 0.24, respectively. The average standard deviation of gross tumor volume calculated from the 10 breathing phases was 0.81 cm{sup 3} and 1.02 cm{sup 3} for SG-KS-4D-MRI and 4D-CT, respectively (P=.012). Conclusions: A novel SG-KS-4D-MRI acquisition method capable of reconstructing rebinning artifact–free, high-resolution 4D-MRI images was used to quantify pancreas tumor motion. The resultant pancreatic tumor motion trajectories agreed well with 2D-cine-MRI and 4D-CT. The pancreatic tumor volumes shown in the different phases for the SG-KS-4D-MRI were statistically significantly more consistent than those in the 4D-CT.« less

A pancreatic tumor-specific biomarker characterized in humans and mice as an immunogenic onco-glycoprotein is efficient in dendritic cell vaccination

PubMed Central

Collignon, Aurélie; Perles-Barbacaru, Adriana Teodora; Robert, Stéphane; Silvy, Françoise; Martinez, Emmanuelle; Crenon, Isabelle; Germain, Sébastien; Garcia, Stéphane; Viola, Angèle; Lombardo, Dominique

2015-01-01

Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC. PMID:26405163

Quantitative CT analysis for the preoperative prediction of pathologic grade in pancreatic neuroendocrine tumors

NASA Astrophysics Data System (ADS)

Chakraborty, Jayasree; Pulvirenti, Alessandra; Yamashita, Rikiya; Midya, Abhishek; Gönen, Mithat; Klimstra, David S.; Reidy, Diane L.; Allen, Peter J.; Do, Richard K. G.; Simpson, Amber L.

2018-02-01

Pancreatic neuroendocrine tumors (PanNETs) account for approximately 5% of all pancreatic tumors, affecting one individual per million each year.1 PanNETs are difficult to treat due to biological variability from benign to highly malignant, indolent to very aggressive. The World Health Organization classifies PanNETs into three categories based on cell proliferative rate, usually detected using the Ki67 index and cell morphology: low-grade (G1), intermediate-grade (G2) and high-grade (G3) tumors. Knowledge of grade prior to treatment would select patients for optimal therapy: G1/G2 tumors respond well to somatostatin analogs and targeted or cytotoxic drugs whereas G3 tumors would be targeted with platinum or alkylating agents.2, 3 Grade assessment is based on the pathologic examination of the surgical specimen, biopsy or ne-needle aspiration; however, heterogeneity in the proliferative index can lead to sampling errors.4 Based on studies relating qualitatively assessed shape and enhancement characteristics on CT imaging to tumor grade in PanNET,5 we propose objective classification of PanNET grade with quantitative analysis of CT images. Fifty-five patients were included in our retrospective analysis. A pathologist graded the tumors. Texture and shape-based features were extracted from CT. Random forest and naive Bayes classifiers were compared for the classification of G1/G2 and G3 PanNETs. The best area under the receiver operating characteristic curve (AUC) of 0:74 and accuracy of 71:64% was achieved with texture features. The shape-based features achieved an AUC of 0:70 and accuracy of 78:73%.

Management of Respiration-Induced Motion With 4-Dimensional Computed Tomography (4DCT) for Pancreas Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tai, An, E-mail: atai@mcw.edu; Liang, Zhiwen; Radiation Oncology Center, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan

2013-08-01

Purpose: The purposes of this study were to quantify respiration-induced organ motions for pancreatic cancer patients and to explore strategies to account for these motions. Methods and Materials: Both 3-dimensional computed tomography (3DCT) and 4-dimensional computed tomography (4DCT) scans were acquired sequentially for 15 pancreatic cancer patients, including 10 randomly selected patients and 5 patients selected from a subgroup of patients with large tumor respiratory motions. 3DCTs were fused with 2 sets of 4DCT data at the end of exhale phase (50%) and the end of inhale phase (0%). The target was delineated on the 50% and 0% phase CTmore » sets, and the organs at risk were drawn on the 3DCT. These contours were populated to the CT sets at other respiratory phases based on deformable image registration. Internal target volumes (ITV) were generated by tracing the target contours of all phases (ITV{sub 10}), 3 phases of 0%, 20% and 50% (ITV{sub 3}), and 2 phases of 0% and 50% (ITV{sub 2}). ITVs generated from phase images were compared using percentage of volume overlap, Dice coefficient, geometric centers, and average surface distance. Results: Volume variations of pancreas, kidneys, and liver as a function of respiratory phases were small (<5%) during respiration. For the 10 randomly selected patients, peak-to-peak amplitudes of liver, left kidney, right kidney, and the target along the superior-inferior (SI) direction were 7.9 ± 3.2 mm, 7.1 ± 3.1 mm, 5.7 ± 3.2 mm, and 5.9 ± 2.8 mm, respectively. The percentage of volume overlap and Dice coefficient were 92% ± 1% and 96% ± 1% between ITV{sub 10} and ITV{sub 2} and 96% ± 1% and 98% ± 1% between ITV{sub 10} and ITV{sub 3}, respectively. The percentage of volume overlap between ITV{sub 10} and ITV{sub 3} was 93.6 ± 1.1 for patients with tumor motion >8 mm. Conclusions: Appropriate motion management strategies are proposed for radiation treatment planning of pancreatic tumors based on magnitudes of

Cystic pancreatic tumors (CPT): predictors of malignant behavior.

PubMed

Javle, Milind; Shah, Pankaj; Yu, Jihnhee; Bhagat, Vishal; Litwin, Alan; Iyer, Renuka; Gibbs, John

2007-03-01

Due to widespread use of imaging studies, increasing cystic pancreatic tumor (CPT) cases are being detected. The diagnosis of malignancy in CPT cases requires pancreatectomy. Clinical and laboratory characteristics of CPT may predict underlying malignancy. CPT cases treated between 1994 and 2004 at our institution were included. Pseudocysts were excluded. Serous cystadenoma (SCA), mucinous cystadenoma (MCA), intrapapillary mucinous tumor, cystic endocrine tumor, and lymphoepithelial cysts were classified as benign or pre-malignant. Serous cystadenocarcinoma (SCACA), mucinous cystadenocarcinoma (MCACA), and adenocarcinoma (ACA) were classified as malignant. Thirty-five patients had histological confirmation. Median age was 65 years. Male/female ratio was higher in malignant group (P = 0.0284). Weight loss and abdominal mass were more prevalent in malignant group (P = 0.042 and 0.028, respectively). Malignant lesions were larger, associated with local invasion (superior mesenteric artery (SMA), superior mesenteric vein (SMV), portal vein (PV) complex or celiac encasement) and CA 19-9 elevation. On univariate analyses, local invasion (P = 0.0029), negative surgical intervention (P = 0.0010), presence of ACA (P = 0.0044), or malignant CPT (P = 0.0018) were associated with shorter survival. On a multivariate analysis, local invasion was associated with shorter survival [Hazard ratio (HR) = 4.322, P = 0.0218], while surgical intervention was associated with improved survival (HR = 0.179, P = 0.0124). Male sex, abdominal mass, weight loss, larger tumor size, local invasion, and elevated CA 19-9 were associated with malignant CPT.

Radio frequency-mediated local thermotherapy for destruction of pancreatic tumors using Ni-Au core-shell nanowires

NASA Astrophysics Data System (ADS)

Hopkins, Xiaoping; Gill, Waqas Amin; Kringel, Rosemarie; Wang, Guankui; Hass, Jamie; Acharya, Suresh; Park, Jungrae; Tak Jeon, In; An, Boo Hyun; Lee, Ji Sung; Ryu, Jong Eun; Hill, Rod; McIlroy, David; Kim, Young Keun; Choi, Daniel S.

2017-01-01

We present a novel method of radio frequency (RF)-mediated thermotherapy in tumors by remotely heating nickel (Ni)-gold (Au) core-shell nanowires (CSNWs). Ectopic pancreatic tumors were developed in nude mice to evaluate the thermotherapeutic effects on tumor progression. Tumor ablation was produced by RF-mediated thermotherapy via activation of the paramagnetic properties of the Ni-Au CSNWs. Histopathology demonstrated that heat generated by RF irradiation caused significant cellular death with pyknotic nuclei and nuclear fragmentation dispersed throughout the tumors. These preliminary results suggest that thermotherapy ablation induced via RF activation of nanowires provides a potential alternative therapy for cancer treatment.

Real-time tracking of respiratory-induced tumor motion by dose-rate regulation

NASA Astrophysics Data System (ADS)

Han-Oh, Yeonju Sarah

We have developed a novel real-time tumor-tracking technology, called Dose-Rate-Regulated Tracking (DRRT), to compensate for tumor motion caused by breathing. Unlike other previously proposed tumor-tracking methods, this new method uses a preprogrammed dynamic multileaf collimator (MLC) sequence in combination with real-time dose-rate control. This new scheme circumvents the technical challenge in MLC-based tumor tracking, that is to control the MLC motion in real time, based on real-time detected tumor motion. The preprogrammed MLC sequence describes the movement of the tumor, as a function of breathing phase, amplitude, or tidal volume. The irregularity of tumor motion during treatment is handled by real-time regulation of the dose rate, which effectively speeds up or slows down the delivery of radiation as needed. This method is based on the fact that all of the parameters in dynamic radiation delivery, including MLC motion, are enslaved to the cumulative dose, which, in turn, can be accelerated or decelerated by varying the dose rate. Because commercially available MLC systems do not allow the MLC delivery sequence to be modified in real time based on the patient's breathing signal, previously proposed tumor-tracking techniques using a MLC cannot be readily implemented in the clinic today. By using a preprogrammed MLC sequence to handle the required motion, the task for real-time control is greatly simplified. We have developed and tested the pre- programmed MLC sequence and the dose-rate regulation algorithm using lung-cancer patients breathing signals. It has been shown that DRRT can track the tumor with an accuracy of less than 2 mm for a latency of the DRRT system of less than 0.35 s. We also have evaluated the usefulness of guided breathing for DRRT. Since DRRT by its very nature can compensate for breathing-period changes, guided breathing was shown to be unnecessary for real-time tracking when using DRRT. Finally, DRRT uses the existing dose-rate control

The usefulness of (18)F-FDG PET/MRI fusion image in diagnosing pancreatic tumor: comparison with (18)F-FDG PET/CT.

PubMed

Nagamachi, Shigeki; Nishii, Ryuichi; Wakamatsu, Hideyuki; Mizutani, Youichi; Kiyohara, Shogo; Fujita, Seigo; Futami, Shigemi; Sakae, Tatefumi; Furukoji, Eiji; Tamura, Shozo; Arita, Hideo; Chijiiwa, Kazuo; Kawai, Keiichi

2013-07-01

This study aimed at demonstrating the feasibility of retrospectively fused (18)F FDG-PET and MRI (PET/MRI fusion image) in diagnosing pancreatic tumor, in particular differentiating malignant tumor from benign lesions. In addition, we evaluated additional findings characterizing pancreatic lesions by FDG-PET/MRI fusion image. We analyzed retrospectively 119 patients: 96 cancers and 23 benign lesions. FDG-PET/MRI fusion images (PET/T1 WI or PET/T2WI) were made by dedicated software using 1.5 Tesla (T) MRI image and FDG-PET images. These images were interpreted by two well-trained radiologists without knowledge of clinical information and compared with FDG-PET/CT images. We compared the differential diagnostic capability between PET/CT and FDG-PET/MRI fusion image. In addition, we evaluated additional findings such as tumor structure and tumor invasion. FDG-PET/MRI fusion image significantly improved accuracy compared with that of PET/CT (96.6 vs. 86.6 %). As additional finding, dilatation of main pancreatic duct was noted in 65.9 % of solid types and in 22.6 % of cystic types, on PET/MRI-T2 fusion image. Similarly, encasement of adjacent vessels was noted in 43.1 % of solid types and in 6.5 % of cystic types. Particularly in cystic types, intra-tumor structures such as mural nodule (35.4 %) or intra-cystic septum (74.2 %) were detected additionally. Besides, PET/MRI-T2 fusion image could detect extra benign cystic lesions (9.1 % in solid type and 9.7 % in cystic type) that were not noted by PET/CT. In diagnosing pancreatic lesions, FDG-PET/MRI fusion image was useful in differentiating pancreatic cancer from benign lesions. Furthermore, it was helpful in evaluating relationship between lesions and surrounding tissues as well as in detecting extra benign cysts.

Vitamin E δ-Tocotrienol Augments the Anti-tumor Activity of Gemcitabine and Suppresses Constitutive NF-κB Activation in Pancreatic Cancer

PubMed Central

Husain, Kazim; Francois, Rony A.; Yamauchi, Teruo; Perez, Marta; Sebti, Said M.; Malafa, Mokenge P.

2011-01-01

The nuclear factor-κB (NF-κB) transcription factor functions as a crucial regulator of cell survival and chemoresistance in pancreatic cancer. Recent studies suggest that tocotrienols, which are the unsaturated forms of vitamin E, are a promising class of anti-cancer compounds that inhibit the growth and survival of many cancer cells, including pancreatic cancer. Here, we show that tocotrienols inhibited NF-κB activity and the survival of human pancreatic cancer cells in vitro and in vivo. Importantly, we found the bioactivity of the 4 natural tocotrienol compounds (α-, β-, δ-, and γ-tocotrienol) to be directly related to their ability to suppress NF-κB activity in vitro and in vivo. The most bioactive tocotrienol for pancreatic cancer, δ-tocotrienol, significantly enhanced the efficacy of gemcitabine to inhibit pancreatic cancer growth and survival in vitro and in vivo. Moreover, we found that δ-tocotrienol augmentation of gemcitabine activity in pancreatic cancer cells and tumors is associated with significant suppression of NF-κB activity and the expression of NF-κB transcriptional targets [Bcl-XL, X-linked inhibitor of apoptosis (XIAP), and survivin]. Our study represents the first comprehensive pre-clinical evaluation of the activity of natural vitamin E compounds in pancreatic cancer. Given these results, we are conducting a phase I trial of δ-tocotrienol in patients with pancreatic cancer utilizing pancreatic tumor cell survival and NF-κB signaling components as intermediate biomarkers. Our data also support future clinical investigation of δ-tocotrienol to augment gemcitabine activity in pancreatic cancer. PMID:21971120

Surgical and molecular pathology of pancreatic neoplasms.

PubMed

Hackeng, Wenzel M; Hruban, Ralph H; Offerhaus, G Johan A; Brosens, Lodewijk A A

2016-06-07

Histologic characteristics have proven to be very useful for classifying different types of tumors of the pancreas. As a result, the major tumor types in the pancreas have long been classified based on their microscopic appearance. Recent advances in whole exome sequencing, gene expression profiling, and knowledge of tumorigenic pathways have deepened our understanding of the underlying biology of pancreatic neoplasia. These advances have not only confirmed the traditional histologic classification system, but also opened new doors to early diagnosis and targeted treatment. This review discusses the histopathology, genetic and epigenetic alterations and potential treatment targets of the five major malignant pancreatic tumors - pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, acinar cell carcinoma and pancreatoblastoma.

Ligand stimulation of ErbB4 and a constitutively-active ErbB4 mutant result in different biological responses in human pancreatic tumor cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mill, Christopher P.; Auburn University Harrison School of Pharmacy, Auburn, AL 36849-5501; Gettinger, Kathleen L.

2011-02-15

Pancreatic cancer is the fourth leading cause of cancer death in the United States. Indeed, it has been estimated that 37,000 Americans will die from this disease in 2010. Late diagnosis, chemoresistance, and radioresistance of these tumors are major reasons for poor patient outcome, spurring the search for pancreatic cancer early diagnostic and therapeutic targets. ErbB4 (HER4) is a member of the ErbB family of receptor tyrosine kinases (RTKs), a family that also includes the Epidermal Growth Factor Receptor (EGFR/ErbB1/HER1), Neu/ErbB2/HER2, and ErbB3/HER3. These RTKs play central roles in many human malignancies by regulating cell proliferation, survival, differentiation, invasiveness, motility,more » and apoptosis. In this report we demonstrate that human pancreatic tumor cell lines exhibit minimal ErbB4 expression; in contrast, these cell lines exhibit varied and in some cases abundant expression and basal tyrosine phosphorylation of EGFR, ErbB2, and ErbB3. Expression of a constitutively-dimerized and -active ErbB4 mutant inhibits clonogenic proliferation of CaPan-1, HPAC, MIA PaCa-2, and PANC-1 pancreatic tumor cell lines. In contrast, expression of wild-type ErbB4 in pancreatic tumor cell lines potentiates stimulation of anchorage-independent colony formation by the ErbB4 ligand Neuregulin 1{beta}. These results illustrate the multiple roles that ErbB4 may be playing in pancreatic tumorigenesis and tumor progression.« less

Development of a Novel Preclinical Pancreatic Cancer Research Model: Bioluminescence Image-Guided Focal Irradiation and Tumor Monitoring of Orthotopic Xenografts1

PubMed Central

Tuli, Richard; Surmak, Andrew; Reyes, Juvenal; Hacker-Prietz, Amy; Armour, Michael; Leubner, Ashley; Blackford, Amanda; Tryggestad, Erik; Jaffee, Elizabeth M; Wong, John; DeWeese, Theodore L; Herman, Joseph M

2012-01-01

PURPOSE: We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. MATERIALS AND METHODS: Luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. BLI was correlated to positron emission tomography (PET)/computed tomography (CT) to estimate tumor dimensions. BLI and cone-beam CT (CBCT) were used to compare tumor centroid location and estimate setup error. BLI and CBCT fusion was performed to guide irradiation of tumors using the small animal radiation research platform (SARRP). DNA damage was assessed by γ-H2Ax staining. BLI was used to longitudinally monitor treatment response. RESULTS: Bioluminescence predicted tumor volume (R = 0.8984) and increased linearly as a function of time up to a 10-fold increase in tumor burden. BLI correlated with PET/CT and necropsy specimen in size (P < .05). Two-dimensional BLI centroid accuracy was 3.5 mm relative to CBCT. BLI-guided irradiated pancreatic tumors stained positively for γ-H2Ax, whereas surrounding normal tissues were spared. Longitudinal assessment of irradiated tumors with BLI revealed significant tumor growth delay of 20 days relative to controls. CONCLUSIONS: We have successfully applied the SARRP to a bioluminescent, orthotopic preclinical pancreas cancer model to noninvasively: 1) allow the identification of tumor burden before therapy, 2) facilitate image-guided focal radiation therapy, and 3) allow normalization of tumor burden and longitudinal assessment of treatment response. PMID:22496923

Pancreatic Gastrointestinal Stromal Tumor after Upper Gastrointestinal Hemorrhage and Performance of Whipple Procedure: A Case Report and Literature Review.

PubMed

Aziret, Mehmet; Çetinkünar, Süleyman; Aktaş, Elife; İrkörücü, Oktay; Bali, İlhan; Erdem, Hasan

2015-08-03

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal system. These types of tumors originate from any part of the tract as well as from the intestine, colon, omentum, mesentery or retroperitoneum. GIST is a rare tumor compared to other types of tumors, accounting for less than 1% of all gastrointestinal tumors. A 56-year-old male patient was hospitalized due to an upper gastrointestinal hemorrhage and the start of abdominal pain on the same day. In the upper gastrointestinal endoscopy that was performed, a solitary mass was found in the second section of the duodenum and a blood vessel (Forrest type 2a) was seen. The extent and location of the mass was detected by abdominal tomography. After hemodynamic recovery, a Whipple procedure was performed without any complications. A subsequent histopathological examination detected a c-kit-positive (CD117) pancreatic GIST with high mitotic index. The most effective treatment method for GISTs is surgical resection. In patients with a head of pancreatic GIST, the Whipple procedure can be used more safely and effectively.

Advances in therapeutic vaccines for pancreatic cancer.

PubMed

Plate, Janet M D

2012-08-01

Pancreatic cancer is one of the most difficult-to-treat cancers. Despite surgical resection, radiation and/or chemotherapy, greater than 94% of people with pancreatic cancer do not survive beyond 5 years. In fact, median survival after diagnosis of metastatic pancreatic cancer is 4.5 months. The majority of patients are diagnosed with nonresectable, metastatic disease, and chemotherapy only extends their median survival by less than 2 months with only 18% of those treated surviving beyond 1 year. Despite the severity of their disease, most patients exhibit tumor specific cellular immunity to their pancreatic cancer antigens. Obviously their immunity is ineffective in preventing tumor growth. Recent studies have demonstrated that the tumor microenvironment may hold the key to determining the nature of the tumors' ability to escape from immune attack. Preliminary clinical trials have suggested that blocking these escape mechanisms may result in survival benefit to the patients, and phase I and II clinical trials with tumor vaccines have led to some survival benefits. Perhaps combining therapies directed against immune escape mechanisms with tumor vaccines will result in even greater survival benefit for patients with pancreatic cancer. While therapeutic vaccines for pancreatic cancers have been reviewed previously (Plate, 2011), updates on recent preliminary reports of two clinical vaccine trials are worthy of our attention.

Pancreatic Ductal Adenocarcinoma (PDA) mice lacking Mucin 1 have a profound defect in tumor growth and metastasis

PubMed Central

Besmer, Dahlia M.; Curry, Jennifer M.; Roy, Lopamudra D.; Tinder, Teresa L.; Sahraei, Mahnaz; Schettini, Jorge; Hwang, Sun-Il; Lee, Yong Y.; Gendler, Sandra J.; Mukherjee, Pinku

2011-01-01

MUC1 is over expressed and aberrantly glycosolated in >60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In the present study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared to both KC and KCM. Cell lines derived from KCKO tumors have significantly lower tumorigenic capacity compared to cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared to mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), or matrix metalloproteinase-9 (MMP9). Further, significantly fewer KCKO cells entered the G2M phase of the cell cycle compared to the KCM cells. Proteomics and western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of MAPK, as well as a significant decrease in Nestin and Tubulin α-2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse in order to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. PMID:21558393

[Duodenum-preserving total pancreatic head resection and pancreatic head resection with segmental duodenostomy].

PubMed

Takada, Tadahiro; Yasuda, Hideki; Nagashima, Ikuo; Amano, Hodaka; Yoshiada, Masahiro; Toyota, Naoyuki

2003-06-01

A duodenum-preserving pancreatic head resection (DPPHR) was first reported by Beger et al. in 1980. However, its application has been limited to chronic pancreatitis because of it is a subtotal pancreatic head resection. In 1990, we reported duodenum-preserving total pancreatic head resection (DPTPHR) in 26 cases. This opened the way for total pancreatic head resection, expanding the application of this approach to tumorigenic morbidities such as intraductal papillary mucinous tumor (IMPT), other benign tumors, and small pancreatic cancers. On the other hand, Nakao et al. reported pancreatic head resection with segmental duodenectomy (PHRSD) as an alternative pylorus-preserving pancreatoduodenectomy technique in 24 cases. Hirata et al. also reported this technique as a new pylorus-preserving pancreatoduodenostomy with increased vessel preservation. When performing DPTPHR, the surgeon should ensure adequate duodenal blood supply. Avoidance of duodenal ischemia is very important in this operation, and thus it is necessary to maintain blood flow in the posterior pancreatoduodenal artery and to preserve the mesoduodenal vessels. Postoperative pancreatic functional tests reveal that DPTPHR is superior to PPPD, including PHSRD, because the entire duodenum and duodenal integrity is very important for postoperative pancreatic function.

Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer.

PubMed

Alldinger, Ingo; Dittert, Dag; Peiper, Matthias; Fusco, Alberto; Chiappetta, Gennaro; Staub, Eike; Lohr, Matthias; Jesnowski, Ralf; Baretton, Gustavo; Ockert, Detlef; Saeger, Hans-Detlev; Grützmann, Robert; Pilarsky, Christian

2005-01-01

Pancreatic cancer is one of the leading causes of cancer-related death. Using DNA gene expression analysis based on a custom made Affymetrix cancer array, we investigated the expression pattern of both primary and established pancreatic carcinoma cell lines. We analyzed the gene expression of 5 established pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2 and HPAF II) and 5 primary isolates, 1 of them derived from benign pancreatic duct cells. Out of 1,540 genes which were expressed in at least 3 experiments, we found 122 genes upregulated and 18 downregulated in tumor cell lines compared to benign cells with a fold change >3. Several of the upregulated genes (like Prefoldin 5, ADAM9 and E-cadherin) have been associated with pancreatic cancer before. The other differentially regulated genes, however, play a so far unknown role in the course of human pancreatic carcinoma. By means of immunohistochemistry we could show that thymosin beta-10 (TMSB10), upregulated in tumor cell lines, is expressed in human pancreatic carcinoma, but not in non-neoplastic pancreatic tissue, suggesting a role for TMSB10 in the carcinogenesis of pancreatic carcinoma. Using gene expression profiling of pancreatic cell lines we were able to identify genes differentially expressed in pancreatic adenocarcinoma, which might contribute to pancreatic cancer development. Copyright 2005 S. Karger AG, Basel.

Pancreatic Cancer—Patient Version

Cancer.gov

Pancreatic cancer can form in exocrine cells and neuroendocrine cells. The exocrine type is more common and is usually found at an advanced stage. Pancreatic neuroendocrine tumors are less common but have a better prognosis. Start here to find information on pancreatic cancer treatment, research, and statistics.

Genetics of pancreatic neuroendocrine tumors: implications for the clinic

PubMed Central

Pea, Antonio; Hruban, Ralph H.; Wood, Laura D.

2016-01-01

Pancreatic neuroendocrine tumors (PanNETs) are a common and deadly neoplasm of the pancreas. Although the importance of genetic alterations in PanNETs has been known for many years, recent comprehensive sequencing studies have greatly expanded our knowledge of neuroendocrine tumorigenesis in the pancreas. These studies have identified specific cellular processes that are altered in PanNETs, highlighted alterations with prognostic implications, and pointed to pathways for targeted therapies. In this review, we will discuss the genetic alterations that play a key role in PanNET tumorigenesis, with a specific focus on those alterations with the potential to change the way patients with these neoplasms are diagnosed and treated. PMID:26413978

Pancreatic Lipomatous Hamartoma: A Hitherto Unrecognized Variant.

PubMed

Tanaka, Mariko; Ushiku, Tetsuo; Ikemura, Masako; Takazawa, Yutaka; Igari, Toru; Shimizu, Michio; Yamaguchi, Hiroshi; Fukushima, Noriyoshi; Sakuma, Kei; Arita, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Watadani, Takeyuki; Nakai, Yousuke; Koike, Kazuhiko; Fukayama, Masashi

2018-05-04

Pancreatic masses consisting of lipomatous components clinically include lipoma, liposarcoma, lipomatous pseudohypertrophy of the pancreas, fat-containing neoplasms such as perivascular epithelioid cell tumor, and malignant neoplasm with lipoid degeneration. We present pancreatic lipomatous hamartoma, which has not been reported hitherto. A solid pancreatic mass was detected from a computed tomographic scan check-up in each of 3 cases of Japanese men. Macroscopically, well-demarcated solid lipomatous masses were detected at the uncus, body, and tail of the pancreas, respectively. Microscopically, the masses predominantly consisted of mature adipocytes with no atypia, but contained characteristics components of pancreatic hamartoma, such as small ducts, a well-preserved acinar structure, and/or fibrous stroma. On the basis of the unique features, lack of islets and absence of periductal elastic fibers, these tumors are a distinct variant of pancreatic hamartoma. Furthermore, high-mobility group AT-hook 2 expression in the fibro-adipocytes of this tumor indicated that these cells are an integral component of the pancreatic lipomatous hamartoma. Consequently, the unique tumors described herein are pancreatic lipomatous hamartoma, which must be discriminated from other lipomatous lesions of the pancreas.

Laser immunotherapy for metastatic pancreatic cancer (Conference Presentation)

NASA Astrophysics Data System (ADS)

Zhou, Feifan

2017-02-01

Pancreatic cancer is an extremely malignant disease with high mortality rate. Currently there is no effective therapeutic strategy for highly metastatic pancreatic cancers. Laser immunotherapy (LIT) is a combination therapeutic approach of targeted phototherapy and immunotherapy, which could destroy treated primary tumors with elimination of untreated metastases. LIT affords a remarkable efficacy in suppressing tumor growth in pancreatic tumors in mice, and results in complete tumor regression in many cases. LIT could synergize targeted phototherapy and immunological effects of immunoadjuvant, which represent a promising treatment modality to induce systemic antitumor response through a local intervention, paving the way for the treatment of highly metastatic pancreatic cancers.

Comparison of Liver Tumor Motion With and Without Abdominal Compression Using Cine-Magnetic Resonance Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eccles, Cynthia L.; Patel, Ritesh; Simeonov, Anna K.

2011-02-01

Purpose: Abdominal compression (AC) can be used to reduce respiratory liver motion in patients undergoing liver stereotactic body radiotherapy. The purpose of the present study was to measure the changes in three-dimensional liver tumor motion with and without compression using cine-magnetic resonance imaging. Patients and Methods: A total of 60 patients treated as a part of an institutional research ethics board-approved liver stereotactic body radiotherapy protocol underwent cine T2-weighted magnetic resonance imaging through the tumor centroid in the coronal and sagittal planes. A total of 240 cine-magnetic resonance imaging sequences acquired at one to three images each second for 30-60more » s were evaluated using an in-house-developed template matching tool (based on the coefficient correlation) to measure the magnitude of the tumor motion. The average tumor edge displacements were used to determine the magnitude of changes in the caudal-cranial (CC) and anteroposterior (AP) directions, with and without AC. Results: The mean tumor motion without AC of 11.7 mm (range, 4.8-23.3) in the CC direction was reduced to 9.4 mm (range, 1.6-23.4) with AC. The tumor motion was reduced in both directions (CC and AP) in 52% of the patients and in a single direction (CC or AP) in 90% of the patients. The mean decrease in tumor motion with AC was 2.3 and 0.6 mm in the CC and AP direction, respectively. Increased motion occurred in one or more directions in 28% of patients. Clinically significant (>3 mm) decreases were observed in 40% and increases in <2% of patients in the CC direction. Conclusion: AC can significantly reduce three-dimensional liver tumor motion in most patients, although the magnitude of the reduction was smaller than previously reported.« less

Sensitivity of tumor motion simulation accuracy to lung biomechanical modeling approaches and parameters.

PubMed

Tehrani, Joubin Nasehi; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu; Wang, Jing

2015-11-21

Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right, anterior-posterior, and superior-inferior directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation.

In Vivo Imaging Reveals Significant Tumor Vascular Dysfunction and Increased Tumor Hypoxia-Inducible Factor-1α Expression Induced by High Single-Dose Irradiation in a Pancreatic Tumor Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maeda, Azusa; Department of Medical Biophysics, University of Toronto, Toronto, Ontario; Chen, Yonghong

Purpose: To investigate the effect of high-dose irradiation on pancreatic tumor vasculature and microenvironment using in vivo imaging techniques. Methods and Materials: A BxPC3 pancreatic tumor xenograft was established in a dorsal skinfold window chamber model and a subcutaneous hind leg model. Tumors were irradiated with a single dose of 4, 12, or 24 Gy. The dorsal skinfold window chamber model was used to assess tumor response, vascular function and permeability, platelet and leukocyte adhesion to the vascular endothelium, and tumor hypoxia for up to 14 days after 24-Gy irradiation. The hind leg model was used to monitor tumor size, hypoxia, and vascularitymore » for up to 65 days after 24-Gy irradiation. Tumors were assessed histologically to validate in vivo observations. Results: In vivo fluorescence imaging revealed temporary vascular dysfunction in tumors irradiated with a single dose of 4 to 24 Gy, but most significantly with a single dose of 24 Gy. Vascular functional recovery was observed by 14 days after irradiation in a dose-dependent manner. Furthermore, irradiation with 24 Gy caused platelet and leukocyte adhesion to the vascular endothelium within hours to days after irradiation. Vascular permeability was significantly higher in irradiated tumors compared with nonirradiated controls 14 days after irradiation. This observation corresponded with increased expression of hypoxia-inducible factor-1α in irradiated tumors. In the hind leg model, irradiation with a single dose of 24 Gy led to tumor growth delay, followed by tumor regrowth. Conclusions: Irradiation of the BxPC3 tumors with a single dose of 24 Gy caused transient vascular dysfunction and increased expression of hypoxia-inducible factor-1α. Such biological changes may impact tumor response to high single-dose and hypofractionated irradiation, and further investigations are needed to better understand the clinical outcomes of stereotactic body radiation therapy.« less

Pancreatic islet cell tumor metastasis in multiple endocrine neoplasia type 1: correlation with primary tumor size.

PubMed

Lowney, J K; Frisella, M M; Lairmore, T C; Doherty, G M

1998-12-01

Islet cell tumor (ICT) metastasis is one of the potentially lethal outcomes of multiple endocrine neoplasia type 1 (MEN 1). Management of ICT in patients with MEN 1 is controversial; some advocate resection based on biochemical evidence of progression, whereas others use tumor size to predict the risk of metastasis and the need for resection. This study correlates the size of primary ICT with the presence of metastases. Forty-eight patients with MEN 1 with ICT, from 34 kindreds followed up in our multiple endocrine neoplasia program, were evaluated; 43 of the 48 have been explored for ICT. Metastases to the lymph nodes and liver were documented. Thirty-three percent of patients with pancreatic tumors less than 1 cm in greatest diameter had metastatic disease at surgery and in follow-up, whereas 34.8% of patients with tumors greater than 2 cm in diameter had metastases to lymph nodes or liver. The 2 patients with liver metastases each had primary tumors greater than 2 cm. Follow-up revealed subsequent metastasis in 1 patient. The size of primary tumors in MEN 1 does not correlate with metastatic potential. This is not a good criterion for exploration. Continued follow-up of these patients will be necessary to define the effect of operation on the course of ICT in MEN 1.

Preclinical fluorescent mouse models of pancreatic cancer

NASA Astrophysics Data System (ADS)

Bouvet, Michael; Hoffman, Robert M.

2007-02-01

Here we describe our cumulative experience with the development and preclinical application of several highly fluorescent, clinically-relevant, metastatic orthotopic mouse models of pancreatic cancer. These models utilize the human pancreatic cancer cell lines which have been genetically engineered to selectively express high levels of the bioluminescent green fluorescent (GFP) or red fluorescent protein (RFP). Fluorescent tumors are established subcutaneously in nude mice, and tumor fragments are then surgically transplanted onto the pancreas. Locoregional tumor growth and distant metastasis of these orthotopic implants occurs spontaneously and rapidly throughout the abdomen in a manner consistent with clinical human disease. Highly specific, high-resolution, real-time visualization of tumor growth and metastasis may be achieved in vivo without the need for contrast agents, invasive techniques, or expensive imaging equipment. We have shown a high correlation between florescent optical imaging and magnetic resonance imaging in these models. Alternatively, transplantation of RFP-expressing tumor fragments onto the pancreas of GFP-expressing transgenic mice may be used to facilitate visualization of tumor-host interaction between the pancreatic tumor fragments and host-derived stroma and vasculature. Such in vivo models have enabled us to serially visualize and acquire images of the progression of pancreatic cancer in the live animal, and to demonstrate the real-time antitumor and antimetastatic effects of several novel therapeutic strategies on pancreatic malignancy. These fluorescent models are therefore powerful and reliable tools with which to investigate human pancreatic cancer and therapeutic strategies directed against it.

Development of a mucin4-targeting SPIO contrast agent for effective detection of pancreatic tumor cells in vitro and in vivo.

PubMed

Wu, Shou-Cheng; Chen, Yu-Jen; Lin, Yi-Jan; Wu, Tung-Ho; Wang, Yun-Ming

2013-11-27

In search of a unique and reliable contrast agent targeting pancreatic adenocarcinoma, new multifunctional nanoparticles (MnMEIO-silane-NH2-(MUC4)-mPEG NPs) were successfully developed in this study. Mucin4-expression levels were determined through different imaging studies in a panel of pancreatic tumor cells (HPAC, BxPC-3, and Panc-1) both in vitro and in vivo studies. The in vitro T2-weighted MR imaging study in HPAC and Panc-1 tumor cells treated with NPs showed -89.1 ± 5.7% and -0.9 ± 0.2% contrast enhancement, whereas in in vivo study, it is found to be -81.5 ± 4.5% versus -19.6 ± 5.2% (24 h postinjection, 7.0 T), respectively. The T2-weighted MR and optical imaging studies revealed that the novel contrast agent can specifically and effectively target to mucin4-expressing tumors in nude mice. Hence, it is suggested that MnMEIO-silane-NH2-(MUC4)-mPEG NPs are able to provide an efficient and targeted delivery of MUC4 antibodies to mucin4-expressing pancreatic tumors.

Diagnosis of metastatic pancreatic mesenchymal tumors by endoscopic ultrasound-guided fine-needle aspiration.

PubMed

Varghese, Linda; Ngae, Min Yi; Wilson, Andrew P; Crowder, Clinton D; Gulbahce, H Evin; Pambuccian, Stefan E

2009-11-01

Involvement of the pancreas by metastatic sarcoma is rare, and can prove challenging to differentiate from sarcomatoid carcinomas which occur more commonly. The endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) technique has been successfully used for the diagnosis of pancreatic carcinomas whether primary or metastatic, and is now considered the most effective noninvasive method for the identification of pancreatic metastases. However, to date very few reports detail the diagnosis of mesenchymal neoplasms by EUS-FNA. Herein, we report a series of four patients who underwent EUS-FNA of the pancreas, where the diagnosis of metastatic sarcoma was made based on morphology and ancillary studies. The cases include metastases of leiomyosarcoma, liposarcoma, alveolar rhabdomyosarcoma, and solitary fibrous tumor. The history of a primary sarcoma of the chest wall, mediastinum, and respectively lower extremity was known for the first three of these patients while in the case of the solitary fibrous tumor a remote history of a paraspinal "hemangiopericytoma" was only elicited after the EUS-FNA diagnosis was made. We conclude that EUS-FNA is efficient and accurate in providing a diagnosis of sarcoma, even in patients without a known primary sarcoma, thus allowing institution of therapy without additional biopsies.

Tumor budding cells, cancer stem cells and epithelial-mesenchymal transition-type cells in pancreatic cancer.

PubMed

Karamitopoulou, Eva

2012-01-01

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a 5-year survival rate of less than 5%. Moreover, PDAC escapes early detection and resists treatment. Multiple combinations of genetic alterations are known to occur in PDAC including mutational activation of KRAS, inactivation of p16/CDKN2A and SMAD4 (DPC4) and dysregulation of PTEN/PI3K/AKT signaling. Through their interaction with Wingless-INT pathway, the downstream molecules of these pathways have been implicated in the promotion of epithelial-mesenchymal transition (EMT). Emerging evidence has demonstrated that cancer stem cells (CSCs), small populations of which have been identified in PDAC, and EMT-type cells play critical roles in drug resistance, invasion, and metastasis in pancreatic cancer. EMT may be histologically represented by the presence of tumor budding which is described as the occurrence of single tumor cells or small clusters (<5) of dedifferentiated cells at the invasive front of gastrointestinal (including colorectal, oesophageal, gastric, and ampullary) carcinomas and is linked to poor prognosis. Tumor budding has recently been shown to occur frequently in PDAC and to be associated with adverse clinicopathological features and decreased disease-free and overall survival. The aim of this review is to present a short overview on the morphological and molecular aspects that underline the relationship between tumor budding cells, CSCs, and EMT-type cells in PDAC.

Real-time soft tissue motion estimation for lung tumors during radiotherapy delivery.

PubMed

Rottmann, Joerg; Keall, Paul; Berbeco, Ross

2013-09-01

To provide real-time lung tumor motion estimation during radiotherapy treatment delivery without the need for implanted fiducial markers or additional imaging dose to the patient. 2D radiographs from the therapy beam's-eye-view (BEV) perspective are captured at a frame rate of 12.8 Hz with a frame grabber allowing direct RAM access to the image buffer. An in-house developed real-time soft tissue localization algorithm is utilized to calculate soft tissue displacement from these images in real-time. The system is tested with a Varian TX linear accelerator and an AS-1000 amorphous silicon electronic portal imaging device operating at a resolution of 512 × 384 pixels. The accuracy of the motion estimation is verified with a dynamic motion phantom. Clinical accuracy was tested on lung SBRT images acquired at 2 fps. Real-time lung tumor motion estimation from BEV images without fiducial markers is successfully demonstrated. For the phantom study, a mean tracking error <1.0 mm [root mean square (rms) error of 0.3 mm] was observed. The tracking rms accuracy on BEV images from a lung SBRT patient (≈20 mm tumor motion range) is 1.0 mm. The authors demonstrate for the first time real-time markerless lung tumor motion estimation from BEV images alone. The described system can operate at a frame rate of 12.8 Hz and does not require prior knowledge to establish traceable landmarks for tracking on the fly. The authors show that the geometric accuracy is similar to (or better than) previously published markerless algorithms not operating in real-time.

Sensitivity of Tumor Motion Simulation Accuracy to Lung Biomechanical Modeling Approaches and Parameters

PubMed Central

Tehrani, Joubin Nasehi; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu

2015-01-01

Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the Neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation. PMID:26531324

Dosimetric Advantages of Midventilation Compared With Internal Target Volume for Radiation Therapy of Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lens, Eelco, E-mail: e.lens@amc.uva.nl; Horst, Astrid van der; Versteijne, Eva

2015-07-01

Purpose: The midventilation (midV) approach can be used to take respiratory-induced pancreatic tumor motion into account during radiation therapy. In this study, the dosimetric consequences for organs at risk and tumor coverage of using a midV approach compared with using an internal target volume (ITV) were investigated. Methods and Materials: For each of the 18 patients, 2 treatment plans (25 × 2.0 Gy) were created, 1 using an ITV and 1 using a midV approach. The midV dose distribution was blurred using the respiratory-induced motion from 4-dimensional computed tomography. The resulting planning target volume (PTV) coverage for this blurred dosemore » distribution was analyzed; PTV coverage was required to be at least V{sub 95%} >98%. In addition, the change in PTV size and the changes in V{sub 10Gy}, V{sub 20Gy}, V{sub 30Gy}, V{sub 40Gy}, D{sub mean} and D{sub 2cc} for the stomach and for the duodenum were analyzed; differences were tested for significance using the Wilcoxon signed-rank test. Results: Using a midV approach resulted in sufficient target coverage. A highly significant PTV size reduction of 13.9% (P<.001) was observed. Also, all dose parameters for the stomach and duodenum, except the D{sub 2cc} of the duodenum, improved significantly (P≤.002). Conclusions: By using the midV approach to account for respiratory-induced tumor motion, a significant PTV reduction and significant dose reductions to the stomach and to the duodenum can be achieved when irradiating pancreatic tumors.« less

SU-E-J-182: Reproducibility of Tumor Motion Probability Distribution Function in Stereotactic Body Radiation Therapy of Lung Using Real-Time Tumor-Tracking Radiotherapy System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shiinoki, T; Hanazawa, H; Park, S

2015-06-15

Purpose: We aim to achieve new four-dimensional radiotherapy (4DRT) using the next generation real-time tumor-tracking (RTRT) system and flattening-filter-free techniques. To achieve new 4DRT, it is necessary to understand the respiratory motion of tumor. The purposes of this study were: 1.To develop the respiratory motion analysis tool using log files. 2.To evaluate the reproducibility of tumor motion probability distribution function (PDF) during stereotactic body RT (SBRT) of lung tumor. Methods: Seven patients having fiducial markers closely implanted to the lung tumor were enrolled in this study. The positions of fiducial markers were measured using the RTRT system (Mitsubishi Electronics Co.,more » JP) and recorded as two types of log files during the course of SBRT. For each patients, tumor motion range and tumor motion PDFs in left-right (LR), anterior-posterior (AP) and superior-inferior (SI) directions were calculated using log files of all beams per fraction (PDFn). Fractional PDF reproducibility (Rn) was calculated as Kullback-Leibler (KL) divergence between PDF1 and PDFn of tumor motion. The mean of Rn (Rm) was calculated for each patient and correlated to the patient’s mean tumor motion range (Am). The change of Rm during the course of SBRT was also evluated. These analyses were performed using in-house developed software. Results: The Rm were 0.19 (0.07–0.30), 0.14 (0.07–0.32) and 0.16 (0.09–0.28) in LR, AP and SI directions, respectively. The Am were 5.11 mm (2.58–9.99 mm), 7.81 mm (2.87–15.57 mm) and 11.26 mm (3.80–21.27 mm) in LR, AP and SI directions, respectively. The PDF reproducibility decreased as the tumor motion range increased in AP and SI direction. That decreased slightly through the course of RT in SI direction. Conclusion: We developed the respiratory motion analysis tool for 4DRT using log files and quantified the range and reproducibility of respiratory motion for lung tumors.« less

A study of longitudinal tumor motion in helical tomotherapy using a cylindrical phantom

PubMed Central

Klein, Michael; Gaede, Stewart

2013-01-01

Tumor motion during radiation treatment on a helical tomotherapy unit may create problems due to interplay with motion of the multileaf collimator, gantry rotation, and patient couch translation through the gantry. This study evaluated this interplay effect for typical clinical parameters using a cylindrical phantom consisting of 1386 diode detectors placed on a respiratory motion platform. All combinations of radiation field widths (1, 2.5, and 5 cm) and gantry rotation periods (16, 30, and 60 s) were considered for sinusoidal motions with a period of 4 s and amplitudes of 5, 6, 7, 8, 9, and 10 mm, as well as real patient breathing pattern. Gamma comparisons with 2% dose difference and 2 mm distance to agreement and dose profiles were used for evaluation. The required motion margins were determined for each set of parameters. The required margin size increased with decreasing field width and increasing tumor motion amplitude, but was not affected by rotation period. The plans with the smallest field width of 1 cm have required motion margins approximately equal to the amplitude of motion (±25%), while those with the largest field width of 5 cm had required motion margins approximately equal to 20% of the motion amplitude (±20%). For tumor motion amplitudes below 6 mm and field widths above 1 cm, the required additional motion margins were very small, at a maximum of 2.5 mm for sinusoidal breathing patterns and 1.2 mm for the real patient breathing pattern. PACS numbers: 87.55.km, 87.55.Qr, 87.56.Fc

Pancreatic islet cell tumor

MedlinePlus

... JH, Kastan MB, Tepper JE, eds. Abeloff's Clinical Oncology . 5th ed. Philadelphia, PA: Elsevier Saunders; 2014:chap ... Cancer Network website. NCCN clinical practice guidelines in oncology (NCCN guidelines): pancreatic adenocarcinoma. Version 3.2017. www. ...

Analysis of Lung Tumor Motion in a Large Sample: Patterns and Factors Influencing Precise Delineation of Internal Target Volume

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knybel, Lukas; VŠB-Technical University of Ostrava, Ostrava; Cvek, Jakub, E-mail: Jakub.cvek@fno.cz

Purpose/Objective: To evaluate lung tumor motion during respiration and to describe factors affecting the range and variability of motion in patients treated with stereotactic ablative radiation therapy. Methods and Materials: Log file analysis from online respiratory tumor tracking was performed in 145 patients. Geometric tumor location in the lungs, tumor volume and origin (primary or metastatic), sex, and tumor motion amplitudes in the superior-inferior (SI), latero-lateral (LL), and anterior-posterior (AP) directions were recorded. Tumor motion variability during treatment was described using intrafraction/interfraction amplitude variability and tumor motion baseline changes. Tumor movement dependent on the tumor volume, position and origin, andmore » sex were evaluated using statistical regression and correlation analysis. Results: After analysis of >500 hours of data, the highest rates of motion amplitudes, intrafraction/interfraction variation, and tumor baseline changes were in the SI direction (6.0 ± 2.2 mm, 2.2 ± 1.8 mm, 1.1 ± 0.9 mm, and −0.1 ± 2.6 mm). The mean motion amplitudes in the lower/upper geometric halves of the lungs were significantly different (P<.001). Motion amplitudes >15 mm were observed only in the lower geometric quarter of the lungs. Higher tumor motion amplitudes generated higher intrafraction variations (R=.86, P<.001). Interfraction variations and baseline changes >3 mm indicated tumors contacting mediastinal structures or parietal pleura. On univariate analysis, neither sex nor tumor origin (primary vs metastatic) was an independent predictive factor of different movement patterns. Metastatic lesions in women, but not men, showed significantly higher mean amplitudes (P=.03) and variability (primary, 2.7 mm; metastatic, 4.9 mm; P=.002) than primary tumors. Conclusion: Online tracking showed significant irregularities in lung tumor movement during respiration. Motion amplitude was significantly lower in

A GPU-based framework for modeling real-time 3D lung tumor conformal dosimetry with subject-specific lung tumor motion.

PubMed

Min, Yugang; Santhanam, Anand; Neelakkantan, Harini; Ruddy, Bari H; Meeks, Sanford L; Kupelian, Patrick A

2010-09-07

In this paper, we present a graphics processing unit (GPU)-based simulation framework to calculate the delivered dose to a 3D moving lung tumor and its surrounding normal tissues, which are undergoing subject-specific lung deformations. The GPU-based simulation framework models the motion of the 3D volumetric lung tumor and its surrounding tissues, simulates the dose delivery using the dose extracted from a treatment plan using Pinnacle Treatment Planning System, Phillips, for one of the 3DCTs of the 4DCT and predicts the amount and location of radiation doses deposited inside the lung. The 4DCT lung datasets were registered with each other using a modified optical flow algorithm. The motion of the tumor and the motion of the surrounding tissues were simulated by measuring the changes in lung volume during the radiotherapy treatment using spirometry. The real-time dose delivered to the tumor for each beam is generated by summing the dose delivered to the target volume at each increase in lung volume during the beam delivery time period. The simulation results showed the real-time capability of the framework at 20 discrete tumor motion steps per breath, which is higher than the number of 4DCT steps (approximately 12) reconstructed during multiple breathing cycles.

Targeting inflammation in pancreatic cancer: Clinical translation

PubMed Central

Steele, Colin William; Kaur Gill, Nina Angharad; Jamieson, Nigel Balfour; Carter, Christopher Ross

2016-01-01

Preclinical modelling studies are beginning to aid development of therapies targeted against key regulators of pancreatic cancer progression. Pancreatic cancer is an aggressive, stromally-rich tumor, from which few people survive. Within the tumor microenvironment cellular and extracellular components exist, shielding tumor cells from immune cell clearance, and chemotherapy, enhancing progression of the disease. The cellular component of this microenvironment consists mainly of stellate cells and inflammatory cells. New findings suggest that manipulation of the cellular component of the tumor microenvironment is possible to promote immune cell killing of tumor cells. Here we explore possible immunogenic therapeutic strategies. Additionally extracellular stromal elements play a key role in protecting tumor cells from chemotherapies targeted at the pancreas. We describe the experimental findings and the pitfalls associated with translation of stromally targeted therapies to clinical trial. Finally, we discuss the key inflammatory signal transducers activated subsequent to driver mutations in oncogenic Kras in pancreatic cancer. We present the preclinical findings that have led to successful early trials of STAT3 inhibitors in pancreatic adenocarcinoma. PMID:27096033

Pancreatic Cancer: Multicenter Prospective Data Collection and Analysis by the Hungarian Pancreatic Study Group.

PubMed

Lakatos, Gábor; Balázs, Anita; Kui, Balázs; Gódi, Szilárd; Szücs, Ákos; Szentesi, Andrea; Szentkereszty, Zsolt; Szmola, Richárd; Kelemen, Dezső; Papp, Róbert; Vincze, Áron; Czimmer, József; Pár, Gabriella; Bajor, Judit; Szabó, Imre; Izbéki, Ferenc; Halász, Adrienn; Leindler, László; Farkas, Gyula; Takács, Tamás; Czakó, László; Szepes, Zoltán; Hegyi, Péter; Kahán, Zsuzsanna

2016-06-01

Pancreatic cancer is a devastating disease with poor prognosis. There is very limited information available regarding the epidemiology and treatment strategies of pancreatic cancer in Central Europe. The purpose of the study was to prospectively collect and analyze data of pancreatic cancer in the Hungarian population. The Hungarian Pancreatic Study Group (HPSG) organized prospective, uniform data collection. Altogether 354 patients were enrolled from 14 Hungarian centers. Chronic pancreatitis was present in 3.7% of the cases, while 33.7% of the patients had diabetes. Family history for pancreatic cancer was positive in 4.8%. The most frequent presenting symptoms included pain (63.8%), weight loss (63%) and jaundice (52.5%). The reported frequency of smoking and alcohol consumption was lower than expected (28.5% and 27.4%, respectively). The majority of patients (75.6%) were diagnosed with advanced disease. Most patients (83.6%) had a primary tumor located in the pancreatic head. The histological diagnosis was ductal adenocarcinoma in 90.7% of the cases, while neuroendocrine tumor was present in 5.3%. Biliary stent implantation was performed in 166 patients, 59.2% of them received metal stents. Primary tumor resection was performed in 60 (16.9%) patients. Enteral or biliary bypass was done in 35 and 49 patients, respectively. In a multivariate Cox-regression model, smoking status and presence of gemcitabine-based chemotherapy were identified as independent predictors for overall survival. We report the first data from a large cohort of Hungarian pancreatic cancer patients. We identified smoking status and chemotherapy as independent predictors in this cohort.

Real-time soft tissue motion estimation for lung tumors during radiotherapy delivery

PubMed Central

Rottmann, Joerg; Keall, Paul; Berbeco, Ross

2013-01-01

Purpose: To provide real-time lung tumor motion estimation during radiotherapy treatment delivery without the need for implanted fiducial markers or additional imaging dose to the patient. Methods: 2D radiographs from the therapy beam's-eye-view (BEV) perspective are captured at a frame rate of 12.8 Hz with a frame grabber allowing direct RAM access to the image buffer. An in-house developed real-time soft tissue localization algorithm is utilized to calculate soft tissue displacement from these images in real-time. The system is tested with a Varian TX linear accelerator and an AS-1000 amorphous silicon electronic portal imaging device operating at a resolution of 512 × 384 pixels. The accuracy of the motion estimation is verified with a dynamic motion phantom. Clinical accuracy was tested on lung SBRT images acquired at 2 fps. Results: Real-time lung tumor motion estimation from BEV images without fiducial markers is successfully demonstrated. For the phantom study, a mean tracking error <1.0 mm [root mean square (rms) error of 0.3 mm] was observed. The tracking rms accuracy on BEV images from a lung SBRT patient (≈20 mm tumor motion range) is 1.0 mm. Conclusions: The authors demonstrate for the first time real-time markerless lung tumor motion estimation from BEV images alone. The described system can operate at a frame rate of 12.8 Hz and does not require prior knowledge to establish traceable landmarks for tracking on the fly. The authors show that the geometric accuracy is similar to (or better than) previously published markerless algorithms not operating in real-time. PMID:24007146

Rare case of pancreatic cancer with leptomeningeal carcinomatosis

PubMed Central

Yoo, In Kyung; Lee, Hong Sik; Kim, Chang Duk; Chun, Hoon Jai; Jeen, Yoon Tae; Keum, Bora; Kim, Eun Sun; Choi, Hyuk Soon; Lee, Jae Min; Kim, Seung Han; Nam, Seung Joo; Hyun, Jong Jin

2015-01-01

Leptomeningeal carcinomatosis occurs very rarely in patients with pancreatic cancer. Leptomeningeal carcinomatosis is characterized by multifocal seeding of the leptomeninges by malignant cells that originate from a solid tumor. To the best of our knowledge, brain metastasis from pancreatic cancer is extremely rare. Leptomeningeal carcinomatosis is estimated to occur in 3% to 8% of cases of solid tumors. The clinical manifestation usually involves neurological symptoms, including dizziness, headache, vomiting, nausea, and hemiparesis, symptoms similar to those of meningitis or brain tumors. Diagnostic methods for leptomeningeal carcinomatosis include brain magnetic resonance imaging and cerebrospinal fluid examination. Here, we describe a case of leptomeningeal carcinomatosis in which the primary tumor was later determined to be pancreatic cancer. Brain magnetic resonance imaging findings showed mild enhancement of the leptomeninges, and cerebrospinal fluid cytology was negative at first. However, after repeated spinal taps, atypical cells were observed on cerebrospinal fluid analysis and levels of tumor markers such as carbohydrate antigen 19-9 in cerebrospinal fluid were elevated. Abdominal computed tomography, performed to determine the presence of extracerebral tumors, revealed pancreatic cancer. Pancreatic cancer was confirmed histopathologically on examination of an endoscopic ultrasound-guided fine needle aspiration specimen. PMID:25624740

Tumor-Targeting Salmonella typhimurium A1-R Promotes Tumoricidal CD8+ T Cell Tumor Infiltration and Arrests Growth and Metastasis in a Syngeneic Pancreatic-Cancer Orthotopic Mouse Model.

PubMed

Murakami, Takashi; Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Kiyuna, Tasuku; Hwang, Ho Kyoung; Miyake, Kentaro; Homma, Yuki; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Ichikawa, Yasushi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

2018-01-01

The present study determined the effect of the tumor-targeting strain Salmonella typhimurium A1-R (S. typhimurium A1-R) on CD8 + tumor-infiltrating lymphocytes (TILs) in a syngeneic pancreatic-cancer orthotopic mouse model. The effect of tumor-targeting S. typhimurium A1-R on CD8 + TILs was determined on the Pan02 murine pancreatic-adenocarcinoma implanted orthotopically in the pancreatic tail of C57BL/6 immunocompromised mice. Three weeks after orthotopic implantation, mice were randomized as follows G1: untreated control group (n = 8); and G2: S. typhimurium A1-R-treatment group (n = 8, 1 × 10 7 colony forming units [CFU]/body, iv, weekly, 3 weeks). On the 22nd day from initial treatment, all mice were sacrificed and tumors were harvested. The tumor-volume ratio was defined as ratio of tumor volume on the 22nd day relative to the 1st day. The tumor volume ratio was significantly lower in the S. typhimurium A1-R-treated group (G2) (3.0 ± 2.8) than the untreated control (G1) (39.9 ± 30.7, P < 0.01). Hematoxylin and easin (H&E) staining on tumor sections was performed to evaluate tumor destruction which was classified according to the Evans grading system and found to be much greater in the S. typhimurium A1-R-treated mice (G2). Six mice in G1 had peritoneal dissemination, whereas no mice showed peritoneal dissemination in G2 (P < 0.01). Immunohistochemical staining with anti-mouse CD8 + antibody was performed in order to detect TILs determined by calculating the average number of CD8 + cells in three high power fields (200×) in the treated and untreated tumors. The TIL score was significantly higher in G2 (133.5 ± 32.2) than G1 (45.1 ± 19.4, P < 0.001). The present study demonstrates that S. typhimurium A1-R promotes CD8 + T cell infiltration and inhibition of tumor growth and metastasis. J. Cell. Biochem. 119: 634-639, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Signal Transducer and Activator of Transcription 3, Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer.

PubMed

Nagathihalli, Nagaraj S; Castellanos, Jason A; Shi, Chanjuan; Beesetty, Yugandhar; Reyzer, Michelle L; Caprioli, Richard; Chen, Xi; Walsh, Alex J; Skala, Melissa C; Moses, Harold L; Merchant, Nipun B

2015-12-01

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified signal transducer and activator of transcription (STAT) 3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance. Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1a(cre/+);LSL-Kras(G12D/+);Tgfbr2(flox/flox) (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by matrix-assisted laser desorption/ionization imaging mass spectrometry. Collagen second harmonic generation imaging quantified tumor collagen alignment and density. STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density, and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma, and down-regulation of cytidine deaminase. Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and down-regulation of cytidine deaminase without depletion of tumor stromal content. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Krüppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice.

PubMed

He, Ping; Yang, Jong Won; Yang, Vincent W; Bialkowska, Agnieszka B

2018-04-01

Activating mutations in KRAS are detected in most pancreatic ductal adenocarcinomas (PDACs). Expression of an activated form of KRAS (KrasG12D) in pancreata of mice is sufficient to induce formation of pancreatic intraepithelial neoplasia (PanINs)-a precursor of PDAC. Pancreatitis increases formation of PanINs in mice that express KrasG12D by promoting acinar-to-ductal metaplasia (ADM). We investigated the role of the transcription factor Krüppel-like factor 5 (KLF5) in ADM and KRAS-mediated formation of PanINs. We performed studies in adult mice with conditional disruption of Klf5 (Klf5 fl/fl ) and/or expression of Kras G12D (LSL-Kras G12D ) via Cre ERTM recombinase regulated by an acinar cell-specific promoter (Ptf1a). Activation of Kras G12D and loss of KLF5 was achieved by administration of tamoxifen. Pancreatitis was induced in mice by administration of cerulein; pancreatic tissues were collected, analyzed by histology and immunohistochemistry, and transcriptomes were compared between mice that did or did not express KLF5. We performed immunohistochemical analyses of human tissue microarrays, comparing levels of KLF5 among 96 human samples of PDAC. UN-KC-6141 cells (pancreatic cancer cells derived from Pdx1-Cre;LSL-Kras G12D mice) were incubated with inhibitors of different kinases and analyzed in proliferation assays and by immunoblots. Expression of KLF5 was knocked down with small hairpin RNAs or CRISPR/Cas9 strategies; cells were analyzed in proliferation and gene expression assays, and compared with cells expressing control vectors. Cells were subcutaneously injected into flanks of syngeneic mice and tumor growth was assessed. Of the 96 PDAC samples analyzed, 73% were positive for KLF5 (defined as nuclear staining in more than 5% of tumor cells). Pancreata from Ptf1a-Cre ERTM ;LSL-Kras G12D mice contained ADM and PanIN lesions, which contained high levels of nuclear KLF5 within these structures. In contrast, Ptf1a-Cre ERTM ;LSL-Kras G12D ;Klf5 fl

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT-2 pancreatic cancer mouse model

PubMed Central

Higuchi, Tamami; Yokobori, Takehiko; Naito, Tomoharu; Kakinuma, Chihaya; Hagiwara, Shinji; Nishiyama, Masahiko; Asao, Takayuki

2018-01-01

Prognosis of pancreatic cancer is poor, thus the development of novel therapeutic drugs is necessary. During preclinical studies, appropriate models are essential for evaluating drug efficacy. The present study sought to determine the ideal pancreatic cancer mouse model for reliable preclinical testing. Such a model could accurately reflect human pancreatic cancer phenotypes and predict future clinical trial results. Systemic pathology analysis was performed in an orthotopic transplantation model to prepare model mice for use in preclinical studies, mimicking the progress of human pancreatic cancer. The location and the timing of inoculated cancer cell metastases, pathogenesis and cause of fatality were analyzed. Furthermore, the efficacy of gemcitabine, a key pancreatic cancer drug, was evaluated in this model where liver metastasis and peritoneal dissemination occur. Results indicated that the SUIT-2 orthotopic pancreatic cancer model was similar to the phenotypic sequential progression of human pancreatic cancer, with extra-pancreatic invasion, intra-peritoneal dissemination and other hematogenous organ metastases. Notably, survival was prolonged by administering gemcitabine to mice with metastasized pancreatic cancer. Furthermore, the detailed effects of gemcitabine on the primary tumor and metastatic tumor lesions were pathologically evaluated in mice. The present study indicated the model accurately depicted pancreatic cancer development and metastasis. Furthermore, the detailed effects of pancreatic cancer drugs on the primary tumor and on metastatic tumor lesions. We present this model as a potential new standard for new drug development in pancreatic cancer. PMID:29435042

Holoclone Forming Cells from Pancreatic Cancer Cells Enrich Tumor Initiating Cells and Represent a Novel Model for Study of Cancer Stem Cells

PubMed Central

Tan, Lei; Sui, Xin; Deng, Hongkui; Ding, Mingxiao

2011-01-01

Background Pancreatic cancer is one of the direct causes of cancer-related death. High level of chemoresistance is one of the major obstacles of clinical treatment. In recent years, cancer stem cells have been widely identified and indicated as the origin of chemoresistance in multi-types of solid tumors. Increasing evidences suggest that cancer stem cells reside in the cells capable of forming holoclones continuously. However, in pancreatic cancer, holoclone-forming cells have not been characterized yet. Therefore, the goal of our present study was to indentify the holoclone-forming pancreatic cancer stem cells and develop an in vitro continuous colony formation system, which will greatly facilitate the study of pancreatic cancer stem cells. Methodology/Principal Findings Pancreatic cancer cell line BxPC3 was submitted to monoclonal cultivation to generate colonies. Based on the morphologies, colonies were classified and analyzed for their capacities of secondary colony formation, long-term survival in vitro, tumor formation in vivo, and drug resistance. Flowcytometry and quantitative RT-PCR were performed to detect the expression level of cancer stem cells associated cell surface markers, regulatory genes and microRNAs in distinct types of colonies. Three types of colonies with distinct morphologies were identified and termed as holo-, mero-, and paraclones, in which only holoclones generated descendant colonies of all three types in further passages. Compared to mero- and paraclones, holoclones possessed higher capacities of long-term survival, tumor initiation, and chemoresistance. The preferential expression of cancer stem cells related marker (CXCR4), regulatory genes (BMI1, GLI1, and GLI2) and microRNAs (miR-214, miR-21, miR-221, miR-222 and miR-155) in holoclones were also highlighted. Conclusions/Significance Our results indicate that the pancreatic tumor-initiating cells with high level of chemoresistance were enriched in holoclones derived from BxPC3

Pancreatic Cancer

PubMed Central

Maitra, Anirban; Hruban, Ralph H.

2009-01-01

The past two decades have witnessed an explosion in our understanding of pancreatic cancer, and it is now clear that pancreatic cancer is a disease of inherited (germ-line) and somatic gene mutations. The genes mutated in pancreatic cancer include KRAS2, p16/CDKN2A, TP53, and SMAD4/DPC4, and these are accompanied by a substantial compendium of genomic and transcriptomic alterations that facilitate cell cycle deregulation, cell survival, invasion, and metastases. Pancreatic cancers do not arise de novo, and three distinct precursor lesions have been identified. Experimental models of pancreatic cancer have been developed in genetically engineered mice, which recapitulate the multistep progression of the cognate human disease. Although the putative cell of origin for pancreatic cancer remains elusive, minor populations of cells with stem-like properties have been identified that appear responsible for tumor initiation, metastases, and resistance of pancreatic cancer to conventional therapies. PMID:18039136

CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans

PubMed Central

Beatty, Gregory L.; Chiorean, Elena G.; Fishman, Matthew P.; Saboury, Babak; Teitelbaum, Ursina R.; Sun, Weijing; Huhn, Richard D.; Song, Wenru; Li, Dongguang; Sharp, Leslie L.; Torigian, Drew A.; O’Dwyer, Peter J.; Vonderheide, Robert H.

2012-01-01

Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer. PMID:21436454

Pharmacokinetically Guided Everolimus in Patients With Breast Cancer, Pancreatic Neuroendocrine Tumors, or Kidney Cancer

ClinicalTrials.gov

2016-12-09

Estrogen Receptor-positive Breast Cancer; Gastrinoma; Glucagonoma; HER2-negative Breast Cancer; Insulinoma; Mucositis; Oral Complications; Pancreatic Polypeptide Tumor; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Recurrent Islet Cell Carcinoma; Recurrent Renal Cell Cancer; Somatostatinoma; Stage III Renal Cell Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Renal Cell Cancer

Percutaneous ablation of pancreatic cancer

PubMed Central

D’Onofrio, Mirko; Ciaravino, Valentina; De Robertis, Riccardo; Barbi, Emilio; Salvia, Roberto; Girelli, Roberto; Paiella, Salvatore; Gasparini, Camilla; Cardobi, Nicolò; Bassi, Claudio

2016-01-01

Pancreatic ductal adenocarcinoma is a highly aggressive tumor with an overall 5-year survival rate of less than 5%. Prognosis and treatment depend on whether the tumor is resectable or not, which mostly depends on how quickly the diagnosis is made. Chemotherapy and radiotherapy can be both used in cases of non-resectable pancreatic cancer. In cases of pancreatic neoplasm that is locally advanced, non-resectable, but non-metastatic, it is possible to apply percutaneous treatments that are able to induce tumor cytoreduction. The aim of this article will be to describe the multiple currently available treatment techniques (radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation), their results, and their possible complications, with the aid of a literature review. PMID:27956791

A biomechanical approach for in vivo lung tumor motion prediction during external beam radiation therapy

NASA Astrophysics Data System (ADS)

Karami, Elham; Gaede, Stewart; Lee, Ting-Yim; Samani, Abbas

2015-03-01

Lung Cancer is the leading cause of cancer death in both men and women. Among various treatment methods currently being used in the clinic, External Beam Radiation Therapy (EBRT) is used widely not only as the primary treatment method, but also in combination with chemotherapy and surgery. However, this method may lack desirable dosimetric accuracy because of respiration induced tumor motion. Recently, biomechanical modeling of the respiratory system has become a popular approach for tumor motion prediction and compensation. This approach requires reasonably accurate data pertaining to thoracic pressure variation, diaphragm position and biomechanical properties of the lung tissue in order to predict the lung tissue deformation and tumor motion. In this paper, we present preliminary results of an in vivo study obtained from a Finite Element Model (FEM) of the lung developed to predict tumor motion during respiration.

Ultrasound-enhanced nanotherapy of pancreatic cancer

NASA Astrophysics Data System (ADS)

Rapoport, N.; Nam, K.-H.; Christensen, D. A.; Kennedy, A. M.; Shea, J. E.; Scaife, C. L.

2010-03-01

The paper reports in vivo results of ultrasonic nanotherapy of orthotopically grown pancreatic cancer. Phase-shift paclitaxel (PTX) loaded perfluoropentane (PFP) nanoemusions combined with tumor-directed ultrasound have been used with a considerable success for tumor-targeted chemotherapy of gemcitabin (GEM)-refractory pancreatic cancer (PC). The GEM-resistant pancreatic cancer proved sensitive to treatment by a micellar PTX formulation Genexol PM (GEN) andor nanodroplet PTX formulation ndGEN. Due to increased permeability of tumor blood vessels, drug-loaded nanodroplets accumulated in the tumor via passive targeting, which was confirmed by ultrasound imaging. Nanodroplets converted into microbubbles in situ under the action of tumor-directed 1-MHz therapeutic ultrasound. The strongest therapeutic effect was observed for the combination therapy by PTX-loaded nanodroplets, GEM and ultrasound (ndGEN+GEM+ultrasound). This combination therapy resulted in a spectacular tumor regression and in some cases complete tumor resolution. Moreover, formation of metastases was dramatically decreased and ascitis generation was completely suppressed. However for all animal groups, local tumor recurrence was observed after the completion of the treatment indicating that some cancer cells survived the treatment. The recurrent tumors proved more resistant to the repeated therapy than initial tumors.

Von Hippel–Lindau and myotonic dystrophy of Steinert along with pancreatic neuroendocrine tumor and renal clear cell carcinomal neoplasm: Case report and review of the literature

PubMed Central

Addeo, A.; Bini, R.; Viora, T.; Bonaccorsi, L.; Leli, R.

2013-01-01

INTRODUCTION Myotonic dystrophy of Steinert, DM1, is the most common adult muscular dystrophy and generally is not associated to development on multiple site neoplasm. Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome that is associated to tumors such as hemangioblastoma of the retina or central nervous system, clear-cell renal carcinoma (RCC) and endocrine tumors, most commonly pheochromocytoma and non-secretory pancreatic islet cell cancers. No data exist in literature describing the coexistence of both DM1 and VHL. PRESENTATION OF CASE Herein we report a case of renal and pancreatic neoplasm in a young adult female affected by DM1 and VHL simultaneously. DISCUSSION DM1 is due to an unstable trinucleotide (CTG) expansion in the 30 antranslated region of the dystrophia myotonica-protein kinase (DMPK) gene, located on chromosome 19q13.3. Several molecular mechanisms thought to be determining the classical DM phenotype have been shown. VHL disease is characterized by marked phenotypic variability and the most common tumors are hemangioblastomas of the retina or central nervous system, clear-cell renal carcinoma (RCC) and endocrine tumors, most commonly pheochromocytoma and non-secretory pancreatic islet cell cancers. The pancreatic manifestations seen in patients with VHL disease are divided into 2 categories: pancreatic neuroendocrine tumor (PNET) as solid tumors, and cystic lesions, including a simple cyst and serous cystadenoma. The surgical approach for these cistic lesions is to consider as golden standard. Blansfield has proposed 3 criteria to predict metastatic disease of PNET in patients with VHL disease: (1) tumor size greater than or equal to 3 cm; (2) presence of a mutation in exon 3; and (3) tumor doubling time less than 500 d. If the patient has none of these criteria the patient could be followed with physical examination and radiological surveillance on a 2/3 years base.4 If the patient has 1 criterion, the patient

Evaluation of tumor localization in respiration motion-corrected cone-beam CT: Prospective study in lung

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dzyubak, Oleksandr; Kincaid, Russell; Hertanto, Agung

Purpose: Target localization accuracy of cone-beam CT (CBCT) images used in radiation treatment of respiratory disease sites is affected by motion artifacts (blurring and streaking). The authors have previously reported on a method of respiratory motion correction in thoracic CBCT at end expiration (EE). The previous retrospective study was limited to examination of reducing motion artifacts in a small number of patient cases. They report here on a prospective study in a larger group of lung cancer patients to evaluate respiratory motion-corrected (RMC)-CBCT ability to improve lung tumor localization accuracy and reduce motion artifacts in Linac-mounted CBCT images. A secondmore » study goal examines whether the motion correction derived from a respiration-correlated CT (RCCT) at simulation yields similar tumor localization accuracy at treatment. Methods: In an IRB-approved study, 19 lung cancer patients (22 tumors) received a RCCT at simulation, and on one treatment day received a RCCT, a respiratory-gated CBCT at end expiration, and a 1-min CBCT. A respiration monitor of abdominal displacement was used during all scans. In addition to a CBCT reconstruction without motion correction, the motion correction method was applied to the same 1-min scan. Projection images were sorted into ten bins based on abdominal displacement, and each bin was reconstructed to produce ten intermediate CBCT images. Each intermediate CBCT was deformed to the end expiration state using a motion model derived from RCCT. The deformed intermediate CBCT images were then added to produce a final RMC-CBCT. In order to evaluate the second study goal, the CBCT was corrected in two ways, one using a model derived from the RCCT at simulation [RMC-CBCT(sim)], the other from the RCCT at treatment [RMC-CBCT(tx)]. Image evaluation compared uncorrected CBCT, RMC-CBCT(sim), and RMC-CBCT(tx). The gated CBCT at end expiration served as the criterion standard for comparison. Using automatic rigid image

Evaluation of tumor localization in respiration motion-corrected cone-beam CT: prospective study in lung.

PubMed

Dzyubak, Oleksandr; Kincaid, Russell; Hertanto, Agung; Hu, Yu-Chi; Pham, Hai; Rimner, Andreas; Yorke, Ellen; Zhang, Qinghui; Mageras, Gig S

2014-10-01

Target localization accuracy of cone-beam CT (CBCT) images used in radiation treatment of respiratory disease sites is affected by motion artifacts (blurring and streaking). The authors have previously reported on a method of respiratory motion correction in thoracic CBCT at end expiration (EE). The previous retrospective study was limited to examination of reducing motion artifacts in a small number of patient cases. They report here on a prospective study in a larger group of lung cancer patients to evaluate respiratory motion-corrected (RMC)-CBCT ability to improve lung tumor localization accuracy and reduce motion artifacts in Linac-mounted CBCT images. A second study goal examines whether the motion correction derived from a respiration-correlated CT (RCCT) at simulation yields similar tumor localization accuracy at treatment. In an IRB-approved study, 19 lung cancer patients (22 tumors) received a RCCT at simulation, and on one treatment day received a RCCT, a respiratory-gated CBCT at end expiration, and a 1-min CBCT. A respiration monitor of abdominal displacement was used during all scans. In addition to a CBCT reconstruction without motion correction, the motion correction method was applied to the same 1-min scan. Projection images were sorted into ten bins based on abdominal displacement, and each bin was reconstructed to produce ten intermediate CBCT images. Each intermediate CBCT was deformed to the end expiration state using a motion model derived from RCCT. The deformed intermediate CBCT images were then added to produce a final RMC-CBCT. In order to evaluate the second study goal, the CBCT was corrected in two ways, one using a model derived from the RCCT at simulation [RMC-CBCT(sim)], the other from the RCCT at treatment [RMC-CBCT(tx)]. Image evaluation compared uncorrected CBCT, RMC-CBCT(sim), and RMC-CBCT(tx). The gated CBCT at end expiration served as the criterion standard for comparison. Using automatic rigid image registration, each CBCT was

Correlation of monoclonal and polyclonal somatostatin receptor 5 antibodies in pancreatic neuroendocrine tumors

PubMed Central

Kaemmerer, Daniel; Lupp, Amelie; Peter, Luisa; Fischer, Elke; Schulz, Stefan; Klöppel, Günter; Hommann, Merten

2013-01-01

Aims: To evaluate the frequency of somatostatin-receptor 5 (SSTR 5) in pancreatic neuroendocrine tumors by using monoclonal and polyclonal antibodies. Material and Method: we analyzed 66 proven pancreatic neuroendocrine tumors immunohistochemically with monoclonal (clone UMB-4) and polyclonal SSTR 5-antibodies. Immunoreactive score (IRS) and DAKO-score Her2/neu were evaluated. Results: Immunohistochemistry analysis demonstrated for the IRS a significant higher staining of all specimen using the monoclonal antibodies ( IRS SSTR5 poly vs IRS SSTR 5 mono; 20.0% vs 30.3% p < 0.001) by a correlation of 0.21; p = 0.04. For the HER2 score there was also a significant higher staining in the monoclonal group (Her2 SSTR 5 poly vs Her2 SSTR 5 mono; 21.5% vs 28.8% p < 0.001) by a correlation of 0.20; p = 0.08. Conclusion: Both antibodies are useful in staining of SSTR, although UMB-4 demonstrated a 10% higher SSTR 5 staining. Due to the previous underestimated expression rate of SSTR 5, current standards in diagnostics and therapy should be reconsidered. The increasing usage of long-acting pansomatostatin receptor analogues will rise the adverse effects connected to SSTR5 binding. PMID:23236542

IL2RG, identified as overexpressed by RNA-seq profiling of pancreatic intraepithelial neoplasia, mediates pancreatic cancer growth

PubMed Central

Ayars, Michael; O’Sullivan, Eileen; Macgregor-Das, Anne; Shindo, Koji; Kim, Haeryoung; Borges, Michael; Yu, Jun; Hruban, Ralph H.; Goggins, Michael

2017-01-01

Pancreatic ductal adenocarcinoma evolves from precursor lesions, the most common of which is pancreatic intraepithelial neoplasia (PanIN). We performed RNA-sequencing analysis of laser capture microdissected PanINs and normal pancreatic duct cells to identify differentially expressed genes between PanINs and normal pancreatic duct, and between low-grade and high-grade PanINs. One of the most highly overexpressed transcripts identified in PanIN is interleukin-2 receptor subunit gamma (IL2RG) encoding the common gamma chain, IL2Rγ. CRISPR-mediated knockout of IL2RG in orthotopically implanted pancreatic cancer cells resulted in attenuated tumor growth in mice and reduced JAK3 expression in orthotopic tumors. These results indicate that IL2Rγ/JAK3 signaling contributes to pancreatic cancer cell growth in vivo. PMID:29137350

Evaluation of lung tumor motion management in radiation therapy with dynamic MRI

NASA Astrophysics Data System (ADS)

Park, Seyoun; Farah, Rana; Shea, Steven M.; Tryggestad, Erik; Hales, Russell; Lee, Junghoon

2017-03-01

Surrogate-based tumor motion estimation and tracing methods are commonly used in radiotherapy despite the lack of continuous real time 3D tumor and surrogate data. In this study, we propose a method to simultaneously track the tumor and external surrogates with dynamic MRI, which allows us to evaluate their reproducible correlation. Four MRIcompatible fiducials are placed on the patient's chest and upper abdomen, and multi-slice 2D cine MRIs are acquired to capture the lung and whole tumor, followed by two-slice 2D cine MRIs to simultaneously track the tumor and fiducials, all in sagittal orientation. A phase-binned 4D-MRI is first reconstructed from multi-slice MR images using body area as a respiratory surrogate and group-wise registration. The 4D-MRI provides 3D template volumes for different breathing phases. 3D tumor position is calculated by 3D-2D template matching in which 3D tumor templates in 4D-MRI reconstruction and the 2D cine MRIs from the two-slice tracking dataset are registered. 3D trajectories of the external surrogates are derived via matching a 3D geometrical model to the fiducial segmentations on the 2D cine MRIs. We tested our method on five lung cancer patients. Internal target volume from 4D-CT showed average sensitivity of 86.5% compared to the actual tumor motion for 5 min. 3D tumor motion correlated with the external surrogate signal, but showed a noticeable phase mismatch. The 3D tumor trajectory showed significant cycle-to-cycle variation, while the external surrogate was not sensitive enough to capture such variations. Additionally, there was significant phase mismatch between surrogate signals obtained from fiducials at different locations.

Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression.

PubMed

Ferreira, Rute M M; Sancho, Rocio; Messal, Hendrik A; Nye, Emma; Spencer-Dene, Bradley; Stone, Richard K; Stamp, Gordon; Rosewell, Ian; Quaglia, Alberto; Behrens, Axel

2017-10-24

The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both ductal and acinar cells with similar histology but with distinct pathophysiology and marker expression dependent on cell of origin. Whereas acinar-derived tumors exhibited low AGR2 expression and were preceded by pancreatic intraepithelial neoplasias (PanINs), duct-derived tumors displayed high AGR2 and developed independently of a PanIN stage via non-mucinous lesions. Using orthotopic transplantation and chimera experiments, we demonstrate that PanIN-like lesions can be induced by PDAC as bystanders in adjacent healthy tissues, explaining the co-existence of mucinous and non-mucinous lesions and highlighting the need to distinguish between true precursor PanINs and PanIN-like bystander lesions. Our results suggest AGR2 as a tool to stratify PDAC according to cell of origin, highlight that not all PanIN-like lesions are precursors of PDAC, and add an alternative progression route to the current model of PDAC development. Copyright © 2017 Francis Crick Institute. Published by Elsevier Inc. All rights reserved.

Type I Interferon Receptor Expression in Human Pancreatic and Periampullary Cancer Tissue.

PubMed

Booy, Stephanie; Hofland, Leo J; Waaijers, A Marlijn; Croze, Ed; van Koetsveld, Peter M; de Vogel, Lisette; Biermann, Katharina; van Eijck, Casper H J

2015-01-01

Interferons (IFNs) have several anticancer mechanisms. A number of clinical trials have been conducted regarding adjuvant IFN-α therapy in pancreatic cancer. Type I IFNs exert their effect via the type I IFN receptor (IFNAR-1, IFNAR-2c). The aims of the present study were to determine the type I IFN receptor expression in pancreatic and periampullary cancer tissues and to study its relation with clinicopathological factors. Receptor expression was determined by immunohistochemistry in paraffin-embedded cancer tissue of 47 pancreatic and 54 periampullary cancer patients. The results demonstrated that 91.5% of the pancreatic tumors and 88.9% of the periampullary tumors showed expression of IFNAR-1, of which 23.4% and 13.0% were strongly positive, respectively. Regarding IFNAR-2c expression, 68.1% of the pancreatic tumors and 68.5% of the periampullary tumors were positive, of which 4.3% of the pancreatic tumors and none of the periampullary tumors had a strong expression. No statistically significant associations were found between type I IFN receptor expression and clinicopathological factors or survival. Type I IFN receptors are expressed in pancreatic and periampullary cancer tissues although with great intertumoral and intratumoral variability. A small proportion of both tumors showed a strong expression of the IFNAR-1; only a very small percentage of the pancreatic tumors showed strong expression of the IFNAR-2c.

miR-219-1-3p is a negative regulator of the mucin MUC4 expression and is a tumor suppressor in pancreatic cancer.

PubMed

Lahdaoui, F; Delpu, Y; Vincent, A; Renaud, F; Messager, M; Duchêne, B; Leteurtre, E; Mariette, C; Torrisani, J; Jonckheere, N; Van Seuningen, I

2015-02-05

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers in the world with one of the worst outcome. The oncogenic mucin MUC4 has been identified as an actor of pancreatic carcinogenesis as it is involved in many processes regulating pancreatic cancer cell biology. MUC4 is not expressed in healthy pancreas whereas it is expressed very early in pancreatic carcinogenesis. Targeting MUC4 in these early steps may thus appear as a promising strategy to slow-down pancreatic tumorigenesis. miRNA negative regulation of MUC4 could be one mechanism to efficiently downregulate MUC4 gene expression in early pancreatic neoplastic lesions. Using in silico studies, we found two putative binding sites for miR-219-1-3p in the 3'-UTR of MUC4 and showed that miR-219-1-3p expression is downregulated both in PDAC-derived cell lines and human PDAC tissues compared with their normal counterparts. We then showed that miR-219-1-3p negatively regulates MUC4 mucin expression via its direct binding to MUC4 3'-UTR. MiR-219-1-3p overexpression (transient and stable) in pancreatic cancer cell lines induced a decrease of cell proliferation associated with a decrease of cyclin D1 and a decrease of Akt and Erk pathway activation. MiR-219-1-3p overexpression also decreased cell migration. Furthermore, miR-219-1-3p expression was found to be conversely correlated with Muc4 expression in early pancreatic intraepithelial neoplasia lesions of Pdx1-Cre;LSL-Kras(G12D) mice. Most interestingly, in vivo studies showed that miR-219-1-3p injection in xenografted pancreatic tumors in mice decreased both tumor growth and MUC4 mucin expression. Altogether, these results identify miR-219-1-3p as a new negative regulator of MUC4 oncomucin that possesses tumor-suppressor activity in PDAC.

Histone deacetylase (HDAC)-1, -2, -4 and -6 expression in human pancreatic adenocarcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients' survival.

PubMed

Giaginis, Constantinos; Damaskos, Christos; Koutsounas, Ioannis; Zizi-Serbetzoglou, Adamantia; Tsoukalas, Nicolaos; Patsouris, Efstratios; Kouraklis, Gregorios; Theocharis, Stamatios

2015-10-26

Histone deacetylases (HDACs) have been associated with malignant tumor development and progression in humans. HDAC inhibitors (HDACIs) are currently being explored as anti-cancer agents in clinical trials. The present study aimed to evaluate the clinical significance of HDAC-1, -2, -4 and -6 protein expression in pancreatic adenocarcinoma. HDAC-1, -2, -4 and -6 protein expression was assessed immunohistochemically on 70 pancreatic adenocarcinoma tissue specimens and was statistically analyzed with clinicopathological characteristics and patients' survival. Enhanced HDAC-1 expression was significantly associated with increased tumor proliferative capacity (p = 0.0238) and borderline with the absence of lymph node metastases (p = 0.0632). Elevated HDAC-4 expression was significantly associated with the absence of organ metastases (p = 0.0453) and borderline with the absence of lymph node metastases (p = 0.0571) and tumor proliferative capacity (p = 0.0576). Enhanced HDAC-6 expression was significantly associated with earlier histopathological stage (p = 0.0115) and borderline with smaller tumor size (p = 0.0864). Pancreatic adenocarcinoma patients with enhanced HDAC-1 and -6 expression showed significantly longer survival times compared to those with low expression (p = 0.0022 and p = 0.0113, respectively), while a borderline association concerning HDAC-2 expression was noted (p = 0.0634). The present study suggested that HDACs may be implicated in pancreatic malignant disease progression, being considered of clinical utility with potential use as therapeutic targets.

New Onset of Diabetes and Pancreatic Exocrine Insufficiency After Pancreaticoduodenectomy for Benign and Malignant Tumors: A Systematic Review and Meta-analysis of Long-term Results.

PubMed

Beger, Hans G; Poch, Bertram; Mayer, Benjamin; Siech, Marco

2018-02-01

The aim of this study was to assess the frequency and severity of new onset of diabetes mellitus (NODM) and pancreatic exocrine insufficiency (PEI) after pancreaticoduodenectomy (PD) for benign and malignant tumors. When PD is performed on patients for benign tumors, the question of long-term metabolic dysfunctions becomes of importance. Medline/PubMed, Embase, and Cochrane Library were searched for articles reporting results of measuring endocrine and exocrine pancreatic functions after PD. The methodological quality of 19 studies was assessed by means of the Newcastle-Ottawa scale and Moga-Score. The mean weighted overall percentages of NODM and PEI after PD were calculated with a 95% confidence interval (CI). Of 1295 patients, data valid-for-efficacy-analysis are based on 845 patients measuring pancreatic endocrine and on 964 patients determining exocrine functions after PD. The cumulative incidence of NODM was 40 of 275 patients (14.5%; 95% CI: 10.3-18.7) in the benign tumor group, 25 of 161 (15.5%; 95% CI: 9.9-21.2) in the malignant tumor group, and 91 of 409 patients (22.2%; 95% CI: 18.2-26.3) in the benign and malignant tumor group. Comparing the frequency of NODM after PD revealed significant differences between the groups (benign vs benign and malignant P < 0.0121; malignant vs benign and malignant P < 0.0017). Exocrine pancreatic insufficiency was found in the benign tumor group in 76 of 301 patients (25.2%; 95% CI: 20.3-30.7) and in the malignant tumor group in 80 of 163 patients (49.1%, 95% CI: 41.4-56.8) (P < 0.0001). The results of a significant increase of NODM after PD for benign and malignant tumors and a significant decrease of exocrine functions contribute to a rational weighting of metabolic long-term risks following PD.

Four-dimensional multislice computed tomography for determination of respiratory lung tumor motion in conformal radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leter, Edward M.; Cademartiri, Filippo; Levendag, Peter C.

2005-07-01

Purpose: We used four-dimensional multislice spiral computed tomography (MSCT) to determine respiratory lung-tumor motion and compared this strategy to common clinical practice in conformal radiotherapy treatment-planning imaging. Methods and Materials: The entire lung volume of 10 consecutive patients with 14 lung metastases were scanned by a 16-slice MSCT. During the scans, patients were instructed to breathe through a spirometer that was connected to a laptop computer. For each patient, 10 stacks of 1.5-mm slices, equally distributed throughout the respiratory cycle, were reconstructed from the acquired MSCT data. The lung tumors were manually contoured in each data set. For each patient,more » the tumor-volume contours of all data sets were copied to 1 data set, which allowed determination of the volume that encompassed all 10 lung-tumor positions (i.e., the tumor-traversed volume [TTV]) during the respiratory cycle. The TTV was compared with the 10 tumor volumes contoured for each patient, to which an empiric respiratory-motion margin was added. The latter target volumes were designated internal-motion included tumor volume (IMITV). Results: The TTV measurements were significantly smaller than the reference IMITV measurements (5.2 {+-} 10.2 cm{sup 3} and 10.1 {+-} 13.7 cm{sup 3}, respectively). All 10 IMITVs for 2 of the 4 tumors in 1 subject completely encompassed the TTV. All 10 IMITVs for 3 tumors in 2 patients did not show overlap with up to 35% of the corresponding TTV. The 10 IMITVs for the remaining tumors either completely encompassed the corresponding TTV or did not show overlap with up to 26% of the corresponding TTV. Conclusions: We found that individualized determination of respiratory lung-tumor motion by four-dimensional respiratory-gated MSCT represents a better and simple strategy to incorporate periodic physiologic motion compared with a generalized approach. The former strategy can, therefore, improve common and state-of-the-art clinical

PET/CT incidental detection of second tumor in patients investigated for pancreatic neoplasms.

PubMed

Moletta, Lucia; Bissoli, Sergio; Fantin, Alberto; Passuello, Nicola; Valmasoni, Michele; Sperti, Cosimo

2018-05-04

Positron Emission Tomography/computed tomography (PET/CT) is an imaging technique which has a role in the detection and staging malignancies (both in first diagnosis and follow-up). The finding of an unexpected region of FDG (Fluorodeoxyglucose) uptake can occur when performing whole-body FDG-PET, raising the possibility of a second primary tumor. The aim of this study was to evaluate our experience of second primary cancer incidentally discovered during PET/CT examination performed for pancreatic diseases, during the initial work-up or follow-up after surgical resection. In this study, a retrospective evaluation of a prospectively collected data base was performed. Three hundred ninety- nine patients with pancreatic pathology were evaluated by whole body PET/CT imaging from January 2004 to December 2014. Among them, 348 patients were scanned before surgical resection and 51 during the course of their follow-up (pancreatic cancer). Median follow-up time was 29 months (range 14-124). Fifty-six patients (14%) had incidental uptake of FDG in their organs: 31 patients had focal uptake and 25 showed diffuse with or without focal uptake. All patients with focal uptake were investigated, and invasive malignancy was diagnosed in 22 patients: 14 colon, 4 lung, 1 larynx, 1 urothelial, 1 breast cancer, and 1 colon metastasis from pancreatic cancer. Twenty patients underwent resection, and 6 endoscopic removal of colonic polyps. Three patients were not operated for advanced disease, and two patients did not show any pathology (PET/CT false positive). Of the 10 patients investigated for diffuse uptake, no malignancy was found; none of these patients developed a second cancer during the follow-up. As in other malignancies, unexpected FDG uptake can occur in patients having PET/CT investigation for pancreatic diseases. Focal uptake is likely to be a malignancy and deserves further investigations, although the stage and the poor prognosis of primary pancreatic cancer should be

Suppression of Tumor Growth and Muscle Wasting in a Transgenic Mouse Model of Pancreatic Cancer by the Novel Histone Deacetylase Inhibitor AR-42.

PubMed

Henderson, Sally E; Ding, Li-Yun; Mo, Xiaokui; Bekaii-Saab, Tanios; Kulp, Samuel K; Chen, Ching-Shih; Huang, Po-Hsien

2016-12-01

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. This study was aimed at evaluating the efficacy of AR-42 (formerly OSU-HDAC42), a novel histone deacetylase (HDAC) inhibitor currently in clinical trials, in suppressing tumor growth and/or cancer-induced muscle wasting in murine models of PDAC. The in vitro antiproliferative activity of AR-42 was evaluated in six human pancreatic cancer cell lines (AsPC-1, COLO-357, PANC-1, MiaPaCa-2, BxPC-3, SW1990). AsPC-1 subcutaneous xenograft and transgenic KP fl/fl C (LSL-Kras G12D ;Trp53 flox/flox ;Pdx-1-Cre) mouse models of pancreatic cancer were used to evaluate the in vivo efficacy of AR-42 in suppressing tumor growth and/or muscle wasting. Growth suppression in AR-42-treated cells was observed in all six human pancreatic cancer cell lines with dose-dependent modulation of proliferation and apoptotic markers, which was associated with the hallmark features of HDAC inhibition, including p21 upregulation and histone H3 hyperacetylation. Oral administration of AR-42 at 50 mg/kg every other day resulted in suppression of tumor burden in the AsPC-1 xenograft and KP fl/fl C models by 78% and 55%, respectively, at the end of treatment. Tumor suppression was associated with HDAC inhibition, increased apoptosis, and inhibition of proliferation. Additionally, AR-42 as a single agent preserved muscle size and increased grip strength in KP fl/fl C mice. Finally, the combination of AR-42 and gemcitabine in transgenic mice demonstrated a significant increase in survival than either agent alone. These results suggest that AR-42 represents a therapeutically promising strategy for the treatment of pancreatic cancer. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures.

PubMed

Mohamed, Amira; Blanchard, Marie-Pierre; Albertelli, Manuela; Barbieri, Federica; Brue, Thierry; Niccoli, Patricia; Delpero, Jean-Robert; Monges, Genevieve; Garcia, Stephane; Ferone, Diego; Florio, Tullio; Enjalbert, Alain; Moutardier, Vincent; Schonbrunn, Agnes; Gerard, Corinne; Barlier, Anne; Saveanu, Alexandru

2014-10-01

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability. © 2014 Society for Endocrinology.

Pancreatic surgery.

PubMed

Donahue, Timothy R; Reber, Howard A

2013-09-01

To summarize published research on pancreatic surgery over the past year. A number of studies aiming to reduce the costs associated with pancreatic surgery were reported. Retrospective analyses confirmed previous findings that neither the routine use of pancreatic duct stents decreases the rate of fistula formation nor does placement of a drain at the time of surgery change the morbidity in patients who develop one. Minimally invasive approaches, both laparoscopic and robot-assisted, are being performed more frequently to remove pancreatic cancers. A randomized trial confirmed that reinforcement of stapled closure during distal pancreatectomy reduces the rate of fistula formation. Controversy remains over whether small pancreatic neuroendocrine tumors need to be surgically resected or can be treated nonoperatively. Patients with chronic pancreatitis should be screened thoroughly before being offered surgical treatment; two studies reported preoperative factors that can be used to identify those most likely to experience pain relief. Studies published on pancreatic surgery last year focused on a wide-range of topics. The morbidity and mortality of patients undergoing pancreatic surgery continues to improve, and we anticipate that incorporation of these new findings will lead to even better outcomes.

Extracellular matrix composition and rigidity regulate invasive behavior and response to PDT in 3D pancreatic tumor models

NASA Astrophysics Data System (ADS)

Cramer, Gwendolyn; El-Hamidi, Hamid; Jafari, Seyedehrojin; Jones, Dustin P.; Celli, Jonathan P.

2016-03-01

The composition and mechanical compliance of the extracellular matrix (ECM) have been shown to serve as regulators of tumor growth and invasive behavior. These effects may be particularly relevant in tumors of the pancreas, noted for a profound desmoplastic reaction and an abundance of stroma rich in ECM. In view of recent progress in the clinical implementation of photodynamic therapy (PDT) for pancreatic tumors, in this report we examine how ECM composition and rheological properties impact upon invasive behavior and response to PDT in 3D multicellular pancreatic tumor spheroids in ECM environments with characterized rheological properties. Tumor spheroids were cultured initially in attachment-free conditions to form millimeter-sized spheroids that were transplanted into reconstituted ECM microenvironments (Matrigel and Type I Collagen) that were characterized using bulk oscillatory shear rheology. Analysis of growth behavior shows that the soft collagen ECM promoted growth and extensive invasion and this microenvironment was used in subsequent assessment of PDT and chemotherapy response. Evaluation of treatment response revealed that primary tumor nodule growth is inhibited more effectively with PDT, while verteporfin PDT response is significantly enhanced in the ECM-infiltrating populations that are non-responsive to oxaliplatin chemotherapy. This finding is potentially significant, suggesting the potential for PDT to target these clinically problematic invasive populations that are associated with aggressive metastatic progression and chemoresistance. Experiments to further validate and identify the mechanistic basis of this observation are ongoing.

Orchestrating the Tumor Microenvironment to Improve Survival for Patients With Pancreatic Cancer: Normalization, Not Destruction.

PubMed

Whatcott, Clifford J; Han, Haiyong; Von Hoff, Daniel D

2015-01-01

Pancreatic cancer is the fourth leading cause of cancer death in the United States. The microenvironment of pancreatic cancer could be one of the "perfect storms" that support the growth of a cancer. Indeed, pancreatic cancer may be the poster child of a problem with the microenvironment. In this article, we review the rationale and attempts to date on modifying or targeting structural proteins in the microenvironment including hyaluronan (HA) (in primary and metastases), collagen, and SPARC (secreted protein, acidic, and rich in cysteine). Indeed, working in this area has produced a regimen that improves survival for patients with advanced pancreatic cancer (nab-paclitaxel + gemcitabine). In addition, in initial clinical trials, PEGylated hyaluronidase appears promising. We also review a new approach that is different than targeting/destroying the microenvironment and that is orchestrating, reengineering, reprogramming, or normalizing the microenvironment (including normalizing structural proteins, normalizing an immunologically tumor-friendly environment to a less friendly environment, reversing epithelial-to-mesenchymal transition, and so on). We believe this will be most effectively done by agents that have global effects on transcription. There is initial evidence that this can be done by agents such as vitamin D derivatives and other new agents. There is no doubt these opportunities can now be tried in the clinic with hopefully beneficial effects.

Losartan Slows Pancreatic Tumor Progression and Extends Survival of SPARC-Null Mice by Abrogating Aberrant TGFβ Activation

PubMed Central

Arnold, Shanna A.; Rivera, Lee B.; Carbon, Juliet G.; Toombs, Jason E.; Chang, Chi-Lun; Bradshaw, Amy D.; Brekken, Rolf A.

2012-01-01

Pancreatic adenocarcinoma, a desmoplastic disease, is the fourth leading cause of cancer-related death in the Western world due, in large part, to locally invasive primary tumor growth and ensuing metastasis. SPARC is a matricellular protein that governs extracellular matrix (ECM) deposition and maturation during tissue remodeling, particularly, during wound healing and tumorigenesis. In the present study, we sought to determine the mechanism by which lack of host SPARC alters the tumor microenvironment and enhances invasion and metastasis of an orthotopic model of pancreatic cancer. We identified that levels of active TGFβ1 were increased significantly in tumors grown in SPARC-null mice. TGFβ1 contributes to many aspects of tumor development including metastasis, endothelial cell permeability, inflammation and fibrosis, all of which are altered in the absence of stromal-derived SPARC. Given these results, we performed a survival study to assess the contribution of increased TGFβ1 activity to tumor progression in SPARC-null mice using losartan, an angiotensin II type 1 receptor antagonist that diminishes TGFβ1 expression and activation in vivo. Tumors grown in SPARC-null mice progressed more quickly than those grown in wild-type littermates leading to a significant reduction in median survival. However, median survival of SPARC-null animals treated with losartan was extended to that of losartan-treated wild-type controls. In addition, losartan abrogated TGFβ induced gene expression, reduced local invasion and metastasis, decreased vascular permeability and altered the immune profile of tumors grown in SPARC-null mice. These data support the concept that aberrant TGFβ1-activation in the absence of host SPARC contributes significantly to tumor progression and suggests that SPARC, by controlling ECM deposition and maturation, can regulate TGFβ availability and activation. PMID:22348081

Radiosensitizing Pancreatic Cancer Xenografts by an Implantable Micro-Oxygen Generator.

PubMed

Cao, Ning; Song, Seung Hyun; Maleki, Teimour; Shaffer, Michael; Stantz, Keith M; Cao, Minsong; Kao, Chinghai; Mendonca, Marc S; Ziaie, Babak; Ko, Song-Chu

2016-04-01

Over the past decades, little progress has been made to improve the extremely low survival rates in pancreatic cancer patients. Extreme hypoxia observed in pancreatic tumors contributes to the aggressive and metastatic characteristics of this tumor and can reduce the effectiveness of conventional radiation therapy and chemotherapy. In an attempt to reduce hypoxia-induced obstacles to effective radiation treatment, we used a novel device, the implantable micro-oxygen generator (IMOG), for in situ tumor oxygenation. After subcutaneous implantation of human pancreatic xenograft tumors in athymic rats, the IMOG was wirelessly powered by ultrasonic waves, producing 30 μA of direct current (at 2.5 V), which was then utilized to electrolyze water and produce oxygen within the tumor. Significant oxygen production by the IMOG was observed and corroborated using the NeoFox oxygen sensor dynamically. To test the radiosensitization effect of the newly generated oxygen, the human pancreatic xenograft tumors were subcutaneously implanted in nude mice with either a functional or inactivated IMOG device. The tumors in the mice were then exposed to ultrasonic power for 10 min, followed by a single fraction of 5 Gy radiation, and tumor growth was monitored thereafter. The 5 Gy irradiated tumors containing the functional IMOG exhibited tumor growth inhibition equivalent to that of 7 Gy irradiated tumors that did not contain an IMOG. Our study confirmed that an activated IMOG is able to produce sufficient oxygen to radiosensitize pancreatic tumors, enhancing response to single-dose radiation therapy.

COMPARING THE ENZYME REPLACEMENT THERAPY COST IN POST PANCREATECTOMY PATIENTS DUE TO PANCREATIC TUMOR AND CHRONIC PANCREATITIS.

PubMed

Fragoso, Anna Victoria; Pedroso, Martha Regina; Herman, Paulo; Montagnini, André Luis

2016-01-01

Among late postoperative complications of pancreatectomy are the exocrine and endocrine pancreatic insufficiencies. The presence of exocrine pancreatic insufficiency imposes, as standard treatment, pancreatic enzyme replacement. Patients with chronic pancreatitis, with intractable pain or any complications with surgical treatment, are likely to present exocrine pancreatic insufficiency or have this condition worsened requiring adequate dose of pancreatic enzymes. The aim of this study is to compare the required dose of pancreatic enzyme and the enzyme replacement cost in post pancreatectomy patients with and without chronic pancreatitis. Observational cross-sectional study. In the first half of 2015 patients treated at the clinic of the Department of Gastrointestinal Surgery at Hospital das Clínicas, Universidade de São Paulo, Brazil, who underwent pancreatectomy for at least 6 months and in use of enzyme replacement therapy were included in this series. The study was approved by the Research Ethics Committee. The patients were divided into two groups according to the presence or absence of chronic pancreatitis prior to pancreatic surgery. For this study, P<0.05 was considered statistically significant. The annual cost of the treatment was R$ 2150.5 ± 729.39; R$ 2118.18 ± 731.02 in patients without pancreatitis and R$ 2217.74 ± 736.30 in patients with pancreatitis. There was no statistically significant difference in the cost of treatment of enzyme replacement post pancreatectomy in patients with or without chronic pancreatitis prior to surgical indication.

Pancreatic neuroendocrine tumors containing areas of iso- or hypoattenuation in dynamic contrast-enhanced computed tomography: Spectrum of imaging findings and pathological grading.

PubMed

Hyodo, Ryota; Suzuki, Kojiro; Ogawa, Hiroshi; Komada, Tomohiro; Naganawa, Shinji

2015-11-01

To evaluate dynamic contrast-enhanced computed tomography (CT) features of pancreatic neuroendocrine tumors (PNETs) containing areas of iso- or hypoattenuation and the relationship with pathological grading. Between June 2006 and March 2014, 61 PNETs in 58 consecutive patients (29 male, 29 female; median-age 55 years), which were surgically diagnosed, underwent preoperative dynamic contrast-enhanced CT. PNETs were classified based on contrast enhancement patterns in the pancreatic phase: iso/hypo-PNETs were defined as tumors containing areas of iso- or hypoattenuation except for cystic components, and hyper-PNETs were tumors showing hyperattenuation over the whole area. CT findings and contrast-enhancement patterns of the tumors were evaluated retrospectively by two radiologists and compared with the pathological grading. Iso/hypo-PNETs comprised 26 tumors, and hyper-PNETs comprised 35 tumors. Not only hyper-PNETs but also most iso/hypo-PNETs showed peak enhancement in the pancreatic phase and a washout from the portal venous phase to the delayed phase. Iso/hypo-PNETs showed larger tumor size than the hyper-PNETs (mean, 3.7 cm vs. 1.6 cm; P<0.001), and were significantly correlated with unclear tumor margins (n=4 vs. n=0; P=0.029), the existence of cystic components (n=10 vs. n=3; P=0.006), intratumoral blood vessels in the early arterial phase (n=13 vs. n=3; P<0.001), and a smooth rim enhancement in the delayed phase (n=12 vs. n=6; P=0.019). Iso/hypo-PNETs also showed significantly higher pathological grading (WHO 2010 classification; iso/hypo, G1=14, G2=11, G3=1; hyper, G1=34, G2=1; P<0.001). PNETs containing iso/hypo-areas showed a rapid enhancement pattern as well as hyper-PNETs, various radiological features and higher malignant potential. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Early Therapy Evaluation of Combined Anti-DR5 Antibody and Gemcitabine in Orthotopic Pancreatic Tumor Xenografts by Diffusion Weighted Magnetic Resonance Imaging

PubMed Central

Kim, Hyunki; Morgan, Desiree E.; Buchsbaum, Donald J.; Zeng, Huadong; Grizzle, William E.; Warram, Jason M.; Stockard, Cecil R.; McNally, Lacey R.; Long, Joshua W.; Sellers, Jeffrey C.; Forero, Andres; Zinn, Kurt R.

2008-01-01

Early therapeutic efficacy of anti-DR5 antibody (TRA-8) combined with gemcitabine was measured using diffusion-weighted magnetic resonance imaging (DWI) in an orthotopic pancreatic tumor model. Groups 1–4 of SCID mice (n=5–7/group) bearing orthotopically implanted, luciferase-positive human pancreatic tumors (MIA PaCa-2) were subsequently (4–5 weeks thereafter) injected with saline (control), gemcitabine (120mg/kg), TRA-8 (200μg), or TRA-8 combined with gemcitabine, respectively, on day 0. DWI, anatomical MRI, and bioluminescence imaging were performed on days 0, 1, 2, and 3 after treatment. Three tumors from each group were collected randomly on day 3 after imaging, and TUNEL staining was performed to quantify apoptotic cellularity. At just 1 day after starting therapy, the changes of apparent diffusion coefficient (ADC) in tumor regions for groups 3 (TRA-8) and 4 (TRA-8/Gem) were 21±9% (mean±SE) and 27±3%, respectively, significantly higher (p <0.05) than those of groups 1 (−1±5%) and 2 (−2±4%). There was no statistical difference in tumor volumes for the groups at this time. The mean ADC values of groups 2–4 gradually increased over 3 days, which were concurrent with tumor-volume regressions and bioluminescence-signal decreases. Apoptotic-cell densities of tumors in groups 1–4 were 0.7±0.4%, 0.6±0.2%, 3.1±0.9%, and 4.7±1.0%, respectively, linearly proportional to the ADC changes on day 1. Further, the ADC changes were highly correlated with the previously reported mean survival times of animals treated with the same agents and doses. This study supports the clinical use of DWI for pancreatic tumor patients for early assessment of drug efficacy. PMID:18922909

Poster - 51: A tumor motion-compensating system with tracking and prediction – a proof-of-concept study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Kaiming; Teo, Peng; Kawalec, Philip

2016-08-15

Purpose: This work reports on the development of a mechanical slider system for the counter-steering of tumor motion in adaptive Radiation Therapy (RT). The tumor motion was tracked using a weighted optical flow algorithm and its position is being predicted with a neural network (NN). Methods: The components of the proposed mechanical counter-steering system includes: (1) an actuator which provides the tumor motion, (2) the motion detection using an optical flow algorithm, (3) motion prediction using a neural network, (4) a control module and (5) a mechanical slider to counter-steer the anticipated motion of the tumor phantom. An asymmetrical cosinemore » function and five patient traces (P1–P5) were used to evaluate the tracking of a 3D printed lung tumor. In the proposed mechanical counter-steering system, both actuator (Zaber NA14D60) and slider (Zaber A-BLQ0070-E01) were programed to move independently with LabVIEW and their positions were recorded by 2 potentiometers (ETI LCP12S-25). The accuracy of this counter-steering system is given by the difference between the two potentiometers. Results: The inherent accuracy of the system, measured using the cosine function, is −0.15 ± 0.06 mm. While the errors when tracking and prediction were included, is (0.04 ± 0.71) mm. Conclusion: A prototype tumor motion counter-steering system with tracking and prediction was implemented. The inherent errors are small in comparison to the tracking and prediction errors, which in turn are small in comparison to the magnitude of tumor motion. The results show that this system is suited for evaluating RT tracking and prediction.« less

Quantification of Esophageal Tumor Motion on Cine-Magnetic Resonance Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lever, Frederiek M.; Lips, Irene M.; Crijns, Sjoerd P.M.

2014-02-01

Purpose: To quantify the movement of esophageal tumors noninvasively on cine-magnetic resonance imaging (MRI) by use of a semiautomatic method to visualize tumor movement directly throughout multiple breathing cycles. Methods and Materials: Thirty-six patients with esophageal tumors underwent MRI. Tumors were located in the upper (8), middle (7), and lower (21) esophagus. Cine-MR images were collected in the coronal and sagittal plane during 60 seconds at a rate of 2 Hz. An adaptive correlation filter was used to automatically track a previously marked reference point. Tumor movement was measured in the craniocaudal (CC), left–right (LR), and anteroposterior (AP) directions andmore » its relationship along the longitudinal axis of the esophagus was investigated. Results: Tumor registration within the individual images was typically done at a millisecond time scale. The mean (SD) peak-to-peak displacements in the CC, AP, and LR directions were 13.3 (5.2) mm, 4.9 (2.5) mm, and 2.7 (1.2) mm, respectively. The bandwidth to cover 95% of excursions from the mean position (c95) was also calculated to exclude outliers caused by sporadic movements. The mean (SD) c95 values were 10.1 (3.8) mm, 3.7 (1.9) mm, and 2.0 (0.9) mm in the CC, AP, and LR dimensions. The end-exhale phase provided a stable position in the respiratory cycle, compared with more variety in the end-inhale phase. Furthermore, lower tumors showed more movement than did higher tumors in the CC and AP directions. Conclusions: Intrafraction tumor movement was highly variable between patients. Tumor position proved the most stable during the respiratory cycle in the end-exhale phase. A better understanding of tumor motion makes it possible to individualize radiation delivery strategies accordingly. Cine-MRI is a successful noninvasive modality to analyze motion for this purpose in the future.« less

Engineered Resistant-Starch (ERS) Diet Shapes Colon Microbiota Profile in Parallel with the Retardation of Tumor Growth in In Vitro and In Vivo Pancreatic Cancer Models.

PubMed

Panebianco, Concetta; Adamberg, Kaarel; Adamberg, Signe; Saracino, Chiara; Jaagura, Madis; Kolk, Kaia; Di Chio, Anna Grazia; Graziano, Paolo; Vilu, Raivo; Pazienza, Valerio

2017-03-27

Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that engineered dietary interventions could be supportive as a

Engineered Resistant-Starch (ERS) Diet Shapes Colon Microbiota Profile in Parallel with the Retardation of Tumor Growth in In Vitro and In Vivo Pancreatic Cancer Models

PubMed Central

Panebianco, Concetta; Adamberg, Kaarel; Adamberg, Signe; Saracino, Chiara; Jaagura, Madis; Kolk, Kaia; Di Chio, Anna Grazia; Graziano, Paolo; Vilu, Raivo; Pazienza, Valerio

2017-01-01

Background/aims: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. Materials and Methods: BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. Results: Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. Conclusion: A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that

Individually optimized contrast-enhanced 4D-CT for radiotherapy simulation in pancreatic ductal adenocarcinoma

PubMed Central

Xue, Ming; Lane, Barton F.; Kang, Min Kyu; Patel, Kruti; Regine, William F.; Klahr, Paul; Wang, Jiahui; Chen, Shifeng; D’Souza, Warren; Lu, Wei

2016-01-01

Purpose: To develop an individually optimized contrast-enhanced (CE) 4D-computed tomography (CT) for radiotherapy simulation in pancreatic ductal adenocarcinomas (PDA). Methods: Ten PDA patients were enrolled. Each underwent three CT scans: a 4D-CT immediately following a CE 3D-CT and an individually optimized CE 4D-CT using test injection. Three physicians contoured the tumor and pancreatic tissues. Image quality scores, tumor volume, motion, tumor-to-pancreas contrast, and contrast-to-noise ratio (CNR) were compared in the three CTs. Interobserver variations were also evaluated in contouring the tumor using simultaneous truth and performance level estimation. Results: Average image quality scores for CE 3D-CT and CE 4D-CT were comparable (4.0 and 3.8, respectively; P = 0.082), and both were significantly better than that for 4D-CT (2.6, P < 0.001). Tumor-to-pancreas contrast results were comparable in CE 3D-CT and CE 4D-CT (15.5 and 16.7 Hounsfield units (HU), respectively; P = 0.21), and the latter was significantly higher than in 4D-CT (9.2 HU, P = 0.001). Image noise in CE 3D-CT (12.5 HU) was significantly lower than in CE 4D-CT (22.1 HU, P = 0.013) and 4D-CT (19.4 HU, P = 0.009). CNRs were comparable in CE 3D-CT and CE 4D-CT (1.4 and 0.8, respectively; P = 0.42), and both were significantly better in 4D-CT (0.6, P = 0.008 and 0.014). Mean tumor volumes were significantly smaller in CE 3D-CT (29.8 cm3, P = 0.03) and CE 4D-CT (22.8 cm3, P = 0.01) than in 4D-CT (42.0 cm3). Mean tumor motion was comparable in 4D-CT and CE 4D-CT (7.2 and 6.2 mm, P = 0.17). Interobserver variations were comparable in CE 3D-CT and CE 4D-CT (Jaccard index 66.0% and 61.9%, respectively) and were worse for 4D-CT (55.6%) than CE 3D-CT. Conclusions: CE 4D-CT demonstrated characteristics comparable to CE 3D-CT, with high potential for simultaneously delineating the tumor and quantifying tumor motion with a single scan. PMID:27782710

Using an external surrogate for predictor model training in real-time motion management of lung tumors.

PubMed

Rottmann, Joerg; Berbeco, Ross

2014-12-01

Precise prediction of respiratory motion is a prerequisite for real-time motion compensation techniques such as beam, dynamic couch, or dynamic multileaf collimator tracking. Collection of tumor motion data to train the prediction model is required for most algorithms. To avoid exposure of patients to additional dose from imaging during this procedure, the feasibility of training a linear respiratory motion prediction model with an external surrogate signal is investigated and its performance benchmarked against training the model with tumor positions directly. The authors implement a lung tumor motion prediction algorithm based on linear ridge regression that is suitable to overcome system latencies up to about 300 ms. Its performance is investigated on a data set of 91 patient breathing trajectories recorded from fiducial marker tracking during radiotherapy delivery to the lung of ten patients. The expected 3D geometric error is quantified as a function of predictor lookahead time, signal sampling frequency and history vector length. Additionally, adaptive model retraining is evaluated, i.e., repeatedly updating the prediction model after initial training. Training length for this is gradually increased with incoming (internal) data availability. To assess practical feasibility model calculation times as well as various minimum data lengths for retraining are evaluated. Relative performance of model training with external surrogate motion data versus tumor motion data is evaluated. However, an internal-external motion correlation model is not utilized, i.e., prediction is solely driven by internal motion in both cases. Similar prediction performance was achieved for training the model with external surrogate data versus internal (tumor motion) data. Adaptive model retraining can substantially boost performance in the case of external surrogate training while it has little impact for training with internal motion data. A minimum adaptive retraining data length of

Molecular biology of pancreatic cancer.

PubMed

Zavoral, Miroslav; Minarikova, Petra; Zavada, Filip; Salek, Cyril; Minarik, Marek

2011-06-28

In spite of continuous research efforts directed at early detection and treatment of pancreatic cancer, the outlook for patients affected by the disease remains dismal. With most cases still being diagnosed at advanced stages, no improvement in survival prognosis is achieved with current diagnostic imaging approaches. In the absence of a dominant precancerous condition, several risk factors have been identified including family history, chronic pancreatitis, smoking, diabetes mellitus, as well as certain genetic disorders such as hereditary pancreatitis, cystic fibrosis, familial atypical multiple mole melanoma, and Peutz-Jeghers and Lynch syndromes. Most pancreatic carcinomas, however, remain sporadic. Current progress in experimental molecular techniques has enabled detailed understanding of the molecular processes of pancreatic cancer development. According to the latest information, malignant pancreatic transformation involves multiple oncogenes and tumor-suppressor genes that are involved in a variety of signaling pathways. The most characteristic aberrations (somatic point mutations and allelic losses) affect oncogenes and tumor-suppressor genes within RAS, AKT and Wnt signaling, and have a key role in transcription and proliferation, as well as systems that regulate the cell cycle (SMAD/DPC, CDKN2A/p16) and apoptosis (TP53). Understanding of the underlying molecular mechanisms should promote development of new methodology for early diagnosis and facilitate improvement in current approaches for pancreatic cancer treatment.

Stages of Pancreatic Neuroendocrine Tumors

MedlinePlus

... Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

Comparison of cytotoxic T lymphocyte responses against pancreatic cancer induced by dendritic cells transfected with total tumor RNA and fusion hybrided with tumor cell

PubMed Central

Chen, Jiang; Li, Hong-Yu; Wang, Di; Shao, Xiao-Dong

2015-01-01

Pancreatic cancer (PC) is a deadly human malignancy. Dendritic cell (DC)-based immunotherapy with whole tumor antigens demonstrates potential efficiency in cancer treatment. Tumor RNA and tumor fusion hybrid cells are sources of whole tumor antigens for preparing DC tumor vaccines. However, the efficacy of these sources in eliciting immune responses against PC has not yet to be directly compared. In the present study, patient-derived PC cells and DCs were fused (DC–tumor hybrids) and primary cultured PC cell-derived total RNA was electroporated into autologous DCs (DC–tumor RNA). The antitumor immune responses induced by DC–tumor hybrids and DC–tumor RNA were compared directly. The results showed that both RNA and hybrid methodologies could induce tumor-specific cytotoxic T lymphocyte (CTL) responses, but pulsing DCs with total tumor RNA could induce a higher frequency of activated CTLs and T-helper cells than fusing DCs with autologous tumor cells. In addition, DC–tumor RNA triggered stronger autologous tumor cell lysis than DC–tumor hybrids. It could be concluded that DCs pulsed with whole tumor RNA are superior to those fused with tumor cells in priming anti-PC CTL responses. Electroporation with total tumor RNA may be more suitable for DC-based PC vaccination. PMID:25736302

CXCL12 Chemokine Expression Suppresses Human Pancreatic Cancer Growth and Metastasis

PubMed Central

Roy, Ishan; Zimmerman, Noah P.; Mackinnon, A. Craig; Tsai, Susan; Evans, Douglas B.; Dwinell, Michael B.

2014-01-01

Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites. PMID:24594697

Inhibition of NFκB and Pancreatic Cancer Cell and Tumor Growth by Curcumin Is Dependent on Specificity Protein Down-regulation*

PubMed Central

Jutooru, Indira; Chadalapaka, Gayathri; Lei, Ping; Safe, Stephen

2010-01-01

Curcumin activates diverse anticancer activities that lead to inhibition of cancer cell and tumor growth, induction of apoptosis, and antiangiogenic responses. In this study, we observed that curcumin inhibits Panc28 and L3.6pL pancreatic cancer cell and tumor growth in nude mice bearing L3.6pL cells as xenografts. In addition, curcumin decreased expression of p50 and p65 proteins and NFκB-dependent transactivation and also decreased Sp1, Sp3, and Sp4 transcription factors that are overexpressed in pancreatic cancer cells. Because both Sp transcription factors and NFκB regulate several common genes such as cyclin D1, survivin, and vascular endothelial growth factor that contribute to the cancer phenotype, we also investigated interactions between Sp and NFκB transcription factors. Results of Sp1, Sp3, and Sp4 knockdown by RNA interference demonstrate that both p50 and p65 are Sp-regulated genes and that inhibition of constitutive or tumor necrosis factor-induced NFκB by curcumin is dependent on down-regulation of Sp1, Sp3, and Sp4 proteins by this compound. Curcumin also decreased mitochondrial membrane potential and induced reactive oxygen species in pancreatic cancer cells, and this pathway is required for down-regulation of Sp proteins in these cells, demonstrating that the mitochondriotoxic effects of curcumin are important for its anticancer activities. PMID:20538607

Reproducibility of Tumor Motion Probability Distribution Function in Stereotactic Body Radiation Therapy of Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang Fan; Medical Physics Graduate Program, Duke University, Durham, North Carolina; Hu Jing

2012-11-01

Purpose: To evaluate the reproducibility of tumor motion probability distribution function (PDF) in stereotactic body radiation therapy (SBRT) of lung cancer using cine megavoltage (MV) images. Methods and Materials: Cine MV images of 20 patients acquired during three-dimensional conformal (6-11 beams) SBRT treatments were retrospectively analyzed to extract tumor motion trajectories. For each patient, tumor motion PDFs were generated per fraction (PDF{sub n}) using three selected 'usable' beams. Patients without at least three usable beams were excluded from the study. Fractional PDF reproducibility (R{sub n}) was calculated as the Dice similarity coefficient between PDF{sub n} to a 'ground-truth' PDF (PDF{submore » g}), which was generated using the selected beams of all fractions. The mean of R{sub n}, labeled as R{sub m}, was calculated for each patient and correlated to the patient's mean tumor motion rang (A{sub m}). Change of R{sub m} during the course of SBRT treatments was also evaluated. Intra- and intersubject coefficient of variation (CV) of R{sub m} and A{sub m} were determined. Results: Thirteen patients had at least three usable beams and were analyzed. The mean of R{sub m} was 0.87 (range, 0.84-0.95). The mean of A{sub m} was 3.18 mm (range, 0.46-7.80 mm). R{sub m} was found to decrease as A{sub m} increases following an equation of R{sub m} = 0.17e{sup -0.9Am} + 0.84. R{sub m} also decreased slightly throughout the course of treatments. Intersubject CV of R{sub m} (0.05) was comparable to intrasubject CV of R{sub m} (range, 0.02-0.09); intersubject CV of A{sub m} (0.73) was significantly greater than intrasubject CV of A{sub m} (range, 0.09-0.24). Conclusions: Tumor motion PDF can be determined using cine MV images acquired during the treatments. The reproducibility of lung tumor motion PDF decreased exponentially as the tumor motion range increased and decreased slightly throughout the course of the treatments.« less

Planning 4-Dimensional Computed Tomography (4DCT) Cannot Adequately Represent Daily Intrafractional Motion of Abdominal Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ge, Jiajia; Santanam, Lakshmi; Noel, Camille

2013-03-15

Purpose: To evaluate whether planning 4-dimensional computed tomography (4DCT) can adequately represent daily motion of abdominal tumors in regularly fractionated and stereotactic body radiation therapy (SBRT) patients. Methods and Materials: Intrafractional tumor motion of 10 patients with abdominal tumors (4 pancreas-fractionated and 6 liver-stereotactic patients) with implanted fiducials was measured based on daily orthogonal fluoroscopic movies over 38 treatment fractions. The needed internal margin for at least 90% of tumor coverage was calculated based on a 95th and fifth percentile of daily 3-dimensional tumor motion. The planning internal margin was generated by fusing 4DCT motion from all phase bins. The disagreementmore » between needed and planning internal margin was analyzed fraction by fraction in 3 motion axes (superior-inferior [SI], anterior-posterior [AP], and left-right [LR]). The 4DCT margin was considered as an overestimation/underestimation of daily motion when disagreement exceeded at least 3 mm in the SI axis and/or 1.2 mm in the AP and LR axes (4DCT image resolution). The underlying reasons for this disagreement were evaluated based on interfractional and intrafractional breathing variation. Results: The 4DCT overestimated daily 3-dimensional motion in 39% of the fractions in 7 of 10 patients and underestimated it in 53% of the fractions in 8 of 10 patients. Median underestimation was 3.9 mm, 3.0 mm, and 1.7 mm in the SI axis, AP axis, and LR axis, respectively. The 4DCT was found to capture irregular deep breaths in 3 of 10 patients, with 4DCT motion larger than mean daily amplitude by 18 to 21 mm. The breathing pattern varied from breath to breath and day to day. The intrafractional variation of amplitude was significantly larger than intrafractional variation (2.7 mm vs 1.3 mm) in the primary motion axis (ie, SI axis). The SBRT patients showed significantly larger intrafractional amplitude variation than fractionated patients (3.0�

Calcified pancreatic and peripancreatic neoplasms: spectrum of pathologies.

PubMed

Verde, Franco; Fishman, Elliot K

2017-11-01

A variety of pancreatic and peripancreatic neoplasms may contain calcifications. We present a review of common to uncommon pancreatic neoplasms that may contain calcifications to include ductal adenocarcinoma, pancreatic neuroendocrine tumors, serous cystadenomas, solid pseudopapillary tumors, intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and lymphoepithelial cysts. In addition, duodenal mucinous adenocarcinoma can present as a peripancreatic mass that may contain calcification. Knowledge of the spectrum of calcification patterns can help the interpreting radiologist provide a meaningful differential.

Reproducibility of tumor motion probability distribution function in stereotactic body radiation therapy of lung cancer.

PubMed

Zhang, Fan; Hu, Jing; Kelsey, Chris R; Yoo, David; Yin, Fang-Fang; Cai, Jing

2012-11-01

To evaluate the reproducibility of tumor motion probability distribution function (PDF) in stereotactic body radiation therapy (SBRT) of lung cancer using cine megavoltage (MV) images. Cine MV images of 20 patients acquired during three-dimensional conformal (6-11 beams) SBRT treatments were retrospectively analyzed to extract tumor motion trajectories. For each patient, tumor motion PDFs were generated per fraction (PDF(n)) using three selected "usable" beams. Patients without at least three usable beams were excluded from the study. Fractional PDF reproducibility (R(n)) was calculated as the Dice similarity coefficient between PDF(n) to a "ground-truth" PDF (PDF(g)), which was generated using the selected beams of all fractions. The mean of R(n), labeled as R(m), was calculated for each patient and correlated to the patient's mean tumor motion rang (A(m)). Change of R(m) during the course of SBRT treatments was also evaluated. Intra- and intersubject coefficient of variation (CV) of R(m) and A(m) were determined. Thirteen patients had at least three usable beams and were analyzed. The mean of R(m) was 0.87 (range, 0.84-0.95). The mean of A(m) was 3.18 mm (range, 0.46-7.80 mm). R(m) was found to decrease as A(m) increases following an equation of R(m) = 0.17e(-0.9Am) + 0.84. R(m) also decreased slightly throughout the course of treatments. Intersubject CV of R(m) (0.05) was comparable to intrasubject CV of R(m) (range, 0.02-0.09); intersubject CV of A(m) (0.73) was significantly greater than intrasubject CV of A(m) (range, 0.09-0.24). Tumor motion PDF can be determined using cine MV images acquired during the treatments. The reproducibility of lung tumor motion PDF decreased exponentially as the tumor motion range increased and decreased slightly throughout the course of the treatments. Copyright © 2012 Elsevier Inc. All rights reserved.

Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302.

PubMed

Wojtkowiak, Jonathan W; Cornnell, Heather C; Matsumoto, Shingo; Saito, Keita; Takakusagi, Yoichi; Dutta, Prasanta; Kim, Munju; Zhang, Xiaomeng; Leos, Rafael; Bailey, Kate M; Martinez, Gary; Lloyd, Mark C; Weber, Craig; Mitchell, James B; Lynch, Ronald M; Baker, Amanda F; Gatenby, Robert A; Rejniak, Katarzyna A; Hart, Charles; Krishna, Murali C; Gillies, Robert J

2015-01-01

Hypoxic niches in solid tumors harbor therapy-resistant cells. Hypoxia-activated prodrugs (HAPs) have been designed to overcome this resistance and, to date, have begun to show clinical efficacy. However, clinical HAPs activity could be improved. In this study, we sought to identify non-pharmacological methods to acutely exacerbate tumor hypoxia to increase TH-302 activity in pancreatic ductal adenocarcinoma (PDAC) tumor models. Three human PDAC cell lines with varying sensitivity to TH-302 (Hs766t > MiaPaCa-2 > SU.86.86) were used to establish PDAC xenograft models. PDAC cells were metabolically profiled in vitro and in vivo using the Seahorse XF system and hyperpolarized (13)C pyruvate MRI, respectively, in addition to quantitative immunohistochemistry. The effect of exogenous pyruvate on tumor oxygenation was determined using electroparamagnetic resonance (EPR) oxygen imaging. Hs766t and MiaPaCa-2 cells exhibited a glycolytic phenotype in comparison to TH-302 resistant line SU.86.86. Supporting this observation is a higher lactate/pyruvate ratio in Hs766t and MiaPaCa xenografts as observed during hyperpolarized pyruvate MRI studies in vivo. Coincidentally, response to exogenous pyruvate both in vitro (Seahorse oxygen consumption) and in vivo (EPR oxygen imaging) was greatest in Hs766t and MiaPaCa models, possibly due to a higher mitochondrial reserve capacity. Changes in oxygen consumption and in vivo hypoxic status to pyruvate were limited in the SU.86.86 model. Combination therapy of pyruvate plus TH-302 in vivo significantly decreased tumor growth and increased survival in the MiaPaCa model and improved survival in Hs766t tumors. Using metabolic profiling, functional imaging, and computational modeling, we show improved TH-302 activity by transiently increasing tumor hypoxia metabolically with exogenous pyruvate. Additionally, this work identified a set of biomarkers that may be used clinically to predict which tumors will be most responsive to

PASSIVE CAVITATION DETECTION DURING PULSED HIFU EXPOSURES OF EX VIVO TISSUES AND IN VIVO MOUSE PANCREATIC TUMORS

PubMed Central

Li, Tong; Chen, Hong; Khokhlova, Tatiana; Wang, Yak-Nam; Kreider, Wayne; He, Xuemei; Hwang, Joo Ha

2014-01-01

Pulsed high-intensity focused ultrasound (pHIFU) has been demonstrated to enhance vascular permeability, disrupt tumor barriers and enhance drug penetration into tumor tissue through acoustic cavitation. Monitoring of cavitation activity during pHIFU treatments and knowing the ultrasound pressure levels sufficient to reliably induce cavitation in a given tissue are therefore very important. Here, three metrics of cavitation activity induced by pHIFU and evaluated by confocal passive cavitation detection were introduced: cavitation probability, cavitation persistence and the level of the broadband acoustic emissions. These metrics were used to characterize cavitation activity in several ex vivo tissue types (bovine tongue and liver and porcine adipose tissue and kidney) and gel phantoms (polyacrylamide and agarose) at varying peak-rarefactional focal pressures (1–12 MPa) during the following pHIFU protocol: frequency 1.1 MHz, pulse duration 1 ms, pulse repetition frequency 1 Hz. To evaluate the relevance of the measurements in ex vivo tissue, cavitation metrics were also investigated and compared in the ex vivo and in vivo murine pancreatic tumors that develop spontaneously in transgenic KPC mice and closely recapitulate human disease in their morphology. The cavitation threshold, defined at 50 % cavitation probability, was found to vary broadly among the investigated tissues (within 2.5–10 MPa), depending mostly on the water-lipid ratio that characterizes the tissue composition. Cavitation persistence and the intensity of broadband emissions depended both on tissue structure and lipid concentration. Both the cavitation threshold and broadband noise emission level were similar between ex vivo and in vivo pancreatic tumor tissue. The largest difference between in vivo and ex vivo settings was found in the pattern of cavitation occurrence throughout pHIFU exposure: it was sporadic in vivo, but ex vivo it decreased rapidly and stopped over the first few pulses

Passive cavitation detection during pulsed HIFU exposures of ex vivo tissues and in vivo mouse pancreatic tumors.

PubMed

Li, Tong; Chen, Hong; Khokhlova, Tatiana; Wang, Yak-Nam; Kreider, Wayne; He, Xuemei; Hwang, Joo Ha

2014-07-01

Pulsed high-intensity focused ultrasound (pHIFU) has been shown to enhance vascular permeability, disrupt tumor barriers and enhance drug penetration into tumor tissue through acoustic cavitation. Monitoring of cavitation activity during pHIFU treatments and knowing the ultrasound pressure levels sufficient to reliably induce cavitation in a given tissue are therefore very important. Here, three metrics of cavitation activity induced by pHIFU and evaluated by confocal passive cavitation detection were introduced: cavitation probability, cavitation persistence and the level of the broadband acoustic emissions. These metrics were used to characterize cavitation activity in several ex vivo tissue types (bovine tongue and liver and porcine adipose tissue and kidney) and gel phantoms (polyacrylamide and agarose) at varying peak-rare factional focal pressures (1-12 MPa) during the following pHIFU protocol: frequency 1.1 MHz, pulse duration 1 ms and pulse repetition frequency 1 Hz. To evaluate the relevance of the measurements in ex vivo tissue, cavitation metrics were also investigated and compared in the ex vivo and in vivo murine pancreatic tumors that develop spontaneously in transgenic KrasLSL.G12 D/+; p53 R172 H/+; PdxCretg/+ (KPC) mice and closely re-capitulate human disease in their morphology. The cavitation threshold, defined at 50% cavitation probability, was found to vary broadly among the investigated tissues (within 2.5-10 MPa), depending mostly on the water-lipid ratio that characterizes the tissue composition. Cavitation persistence and the intensity of broadband emissions depended both on tissue structure and lipid concentration. Both the cavitation threshold and broadband noise emission level were similar between ex vivo and in vivo pancreatic tumor tissue. The largest difference between in vivo and ex vivo settings was found in the pattern of cavitation occurrence throughout pHIFU exposure: it was sporadic in vivo, but it decreased rapidly and stopped

In vivo SPECT imaging with 111In-DOTA-c(RGDfK) to detect early pancreatic cancer in a hamster pancreatic carcinogenesis model.

PubMed

Yoshimoto, Mitsuyoshi; Hayakawa, Takuya; Mutoh, Michihiro; Imai, Toshio; Tsuda, Keisuke; Kimura, Sadaaki; Umeda, Izumi O; Fujii, Hirofumi; Wakabayashi, Keiji

2012-05-01

Early detection of pancreatic cancer is key to overcoming its poor prognosis. α(v)β(3)-integrin is often overexpressed in pancreatic tumor cells, whereas it is scarcely expressed in normal pancreatic cells. In this study, we investigated the usefulness of SPECT imaging with (111)In-1,4,7,10-tetraazacylododecane-N,N',N″,N'''-tetraacetic acid-cyclo-(Arg-Gly-Asp-d-Phe-Lys) [(111)In-DOTA-c(RGDfK)], an imaging probe of α(v)β(3)-integrin, for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. Hamsters were subcutaneously injected with the pancreatic duct carcinogen N-nitrosobis(2-oxopropyl)amine to induce pancreatic cancer. N-nitrosobis(2-oxopropyl)amine-treated hamsters underwent in vivo SPECT with (111)In-DOTA-c(RGDfK). After imaging, the tumor-to-normal pancreatic tissue radioactivity ratios in excised pancreatic samples were measured with autoradiography (ARG) and compared with the immunopathologic findings for α(v)β(3)-integrin. In a mouse model in which inflammation was induced with turpentine, the uptake of (111)In-DOTA-c(RGDfK) in inflammatory regions was evaluated with ARG and compared with that of (18)F-FDG. (111)In-DOTA-c(RGDfK) was clearly visualized in pancreatic cancer lesions as small as 3 mm in diameter. ARG analysis revealed high tumor-to-normal pancreatic tissue radioactivity ratios (4.6 ± 1.0 [mean ± SD] in adenocarcinoma and 3.3 ± 1.4 in atypical hyperplasia). The uptake of (111)In-DOTA-c(RGDfK) strongly correlated with α(v)β(3)-integrin expression. In the inflammatory model, inflammation-to-muscle ratios for (18)F-FDG and (111)In-DOTA-c(RGDfK) were 8.37 ± 4.37 and 1.98 ± 0.60, respectively. These results imply that (111)In-DOTA-c(RGDfK) has a lower rate of false-positive tumor detection than (18)F-FDG. Our findings suggest that SPECT with (111)In-DOTA-c(RGDfK) has great potential for the early and accurate detection of pancreatic cancer.

EFFECTS OF TUMORS ON INHALED PHARMACOLOGIC DRUGS: II. PARTICLE MOTION

EPA Science Inventory

ABSTRACT

Computer simulations were conducted to describe drug particle motion in human lung bifurcations with tumors. The computations used FIDAP with a Cray T90 supercomputer. The objective was to better understand particle behavior as affected by particle characteristics...

Pancreatic endocrine tumor with neoplastic venous thrombus and bilobar liver metastasis. A case report.

PubMed

Barbier, L; Turrini, O; Sarran, A; Delpero, J-R

2010-02-01

We report the case of an asymptomatic 56-year-old woman with a metastatic pancreatic endocrine tumor, fortuitously discovered by abdominal imaging. A CT-scan showed a large mass in the pancreatic tail invading the spleen and stomach; in addition, there was neoplastic thrombus within the spleno-mesentericoportal venous confluence and bilobar liver metastases. Surgical resection was performed in two stages. The first procedure was an extended left pancreatectomy with venous thrombectomy and "clearance" of the left hepatic lobe. During the interval, embolization of the right portal vein was carried out. Right hepatectomy and radiofrequency destruction of residual metastases was then performed. On the basis of completeness of the resection and the histopathological data, the patient did not undergo any adjuvant therapy, in accordance with French guidelines. At 1 year of follow-up, there was no evidence of recurrence. (c) 2010 Elsevier Masson SAS. All rights reserved.

Quantifying Rigid and Nonrigid Motion of Liver Tumors During Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Qianyi, E-mail: xuqianyi@gmail.com; Hanna, George; Grimm, Jimm

2014-09-01

Purpose: To quantify rigid and nonrigid motion of liver tumors using reconstructed 3-dimensional (3D) fiducials from stereo imaging during CyberKnife-based stereotactic body radiation therapy (SBRT). Methods and Materials: Twenty-three liver patients treated with 3 fractions of SBRT were used in this study. After 2 orthogonal kilovoltage images were taken during treatment, the 3D locations of the fiducials were generated by the CyberKnife system and validated using geometric derivations. A total of 4824 pairs of kilovoltage images from start to end of treatment were analyzed. For rigid motion, the rotational angles and translational shifts were reported by aligning 3D fiducial groupsmore » from different image pairs, using least-squares fitting. For nonrigid motion, we quantified interfractional tumor volume variations by using the proportional volume derived from the fiducials, which correlates to the sum of interfiducial distances. The individual fiducial displacements were also reported (1) after rigid corrections and (2) without angle corrections. Results: The proportional volume derived by the fiducials demonstrated a volume-increasing trend in the second (101.9% ± 3.6%) and third (101.0 ± 5.9%) fractions among most patients, possibly due to radiation-induced edema. For all patients, the translational shifts in left-right, anteroposterior, and superoinferior directions were 2.1 ± 2.3 mm, 2.9 ± 2.8 mm, and 6.4 ± 5.5 mm, respectively. The greatest translational shifts occurred in the superoinferior direction, likely due to respiratory motion from the diaphragm. The rotational angles in roll, pitch, and yaw were 1.2° ± 1.8°, 1.8° ± 2.4°, and 1.7° ± 2.1°, respectively. The 3D individual fiducial displacements with rigid corrections were 0.2 ± 0.2 mm and increased to 0.5 ± 0.4 mm without rotational corrections. Conclusions: Accurate 3D locations of internal fiducials can be reconstructed from stereo imaging during treatment. As

Verteporfin heterogeneity in pancreatic adenocarcinoma and the relationship to tumor vasculature and collagen distribution

NASA Astrophysics Data System (ADS)

Vincent, Phuong; Xie, Rui; Nieskoski, Michael; Marra, Kayla; Gunn, Jason; Pogue, Brian W.

2018-02-01

Photodynamic therapy (PDT) has emerged as one promising treatment regimen for several cancer types, with a clinical trial ongoing in pancreatic adenocarcinoma (PDAC). PDT treatment efficacy mainly depends on the combination of light delivery, oxygen availability and photosensitizer uptake, each of which can be limited in pancreas cancer. Therefore, increasing drug uptake in the tumor would make an important impact on treatment outcome. This study was conducted to focus on the issue with drug resistance by examining the relationship between photosensitizer verteporfin and tissue parameters such as collagen and vascular patency. Verteporfin uptake in the tumors was assessed by fluorescence imaging while collagen content and patent vessel area fraction were quantified by evaluating Masson's Trichrome and Lectin pathology staining images. Two tumor cell lines - AsPC-1 and BxPC-3 - were modeled in nude mice to investigate the impact of different tumor microenvironments. Experimental results highlighted the correlation between vascular patency and verteporfin uptake. Collagen content was found to be an independent factor within each tumor line, but a comparison across two tumor types suggested that collagen area of greater than 10% of tumor cross section reflected a lower verteporfin uptake. It was observed that whole-slice tumor quantifications have showcased some interesting trends which could be greatly enhanced and further supported by regional analysis.

[Application of second generation dual-source computed tomography dual-energy scan mode in detecting pancreatic adenocarcinoma].

PubMed

Xue, Hua-dan; Liu, Wei; Sun, Hao; Wang, Xuan; Chen, Yu; Su, Bai-yan; Sun, Zhao-yong; Chen, Fang; Jin, Zheng-yu

2010-12-01

To analyze the clinical value of multiple sequences derived from dual-source computed tomography (DSCT) dual-energy scan mode in detecting pancreatic adenocarcinoma. Totally 23 patients with clinically or pathologically diagnosed pancreatic cancer were enrolled in this retrospective study. DSCT (Definition Flash) was used and dual-energy scan mode was used in their pancreatic parenchyma phase scan (100kVp/230mAs and Sn140kVp/178mAs) . Mono-energetic 60kev, mono-energetic 80kev, mono-energetic 100kev, mono-energetic 120kev, linear blend image, non-linear blend image, and iodine map were acquired. pancreatic parenchyma-tumor CT value difference, ratio of tumor to pancreatic parenchyma, and pancreatic parenchyma-tumor contrast to noise ratio were calculated. One-way ANOVA was used for the comparison of diagnostic values of the above eight different dual-energy derived sequences for pancreatic cancer. The pancreatic parenchyma-tumor CT value difference, ratio of tumor to pancreatic parenchyma, and pancreatic parenchyma-tumor contrast to noise ratio were significantly different among eight sequences (P<0.05) . Mono-energetic 60kev image showed the largest parenchyma-tumor CT value [ (77.53 ± 23.42) HU] , and iodine map showed the lowest tumor/parenchyma enhancement ratio (0.39?0.12) and the largest contrast to noise ratio (4.08 ± 1.46) . Multiple sequences can be derived from dual-energy scan mode with DSCT via multiple post-processing methods. Integration of these sequences may further improve the sensitivity of the multislice spiral CT in the diagnosis of pancreatic cancer.

Various diffusion magnetic resonance imaging techniques for pancreatic cancer

PubMed Central

Tang, Meng-Yue; Zhang, Xiao-Ming; Chen, Tian-Wu; Huang, Xiao-Hua

2015-01-01

Pancreatic cancer is one of the most common malignant tumors and remains a treatment-refractory cancer with a poor prognosis. Currently, the diagnosis of pancreatic neoplasm depends mainly on imaging and which methods are conducive to detecting small lesions. Compared to the other techniques, magnetic resonance imaging (MRI) has irreplaceable advantages and can provide valuable information unattainable with other noninvasive or minimally invasive imaging techniques. Advances in MR hardware and pulse sequence design have particularly improved the quality and robustness of MRI of the pancreas. Diffusion MR imaging serves as one of the common functional MRI techniques and is the only technique that can be used to reflect the diffusion movement of water molecules in vivo. It is generally known that diffusion properties depend on the characterization of intrinsic features of tissue microdynamics and microstructure. With the improvement of the diffusion models, diffusion MR imaging techniques are increasingly varied, from the simplest and most commonly used technique to the more complex. In this review, the various diffusion MRI techniques for pancreatic cancer are discussed, including conventional diffusion weighted imaging (DWI), multi-b DWI based on intra-voxel incoherent motion theory, diffusion tensor imaging and diffusion kurtosis imaging. The principles, main parameters, advantages and limitations of these techniques, as well as future directions for pancreatic diffusion imaging are also discussed. PMID:26753059

Simultaneous tumor and surrogate motion tracking with dynamic MRI for radiation therapy planning

NASA Astrophysics Data System (ADS)

Park, Seyoun; Farah, Rana; Shea, Steven M.; Tryggestad, Erik; Hales, Russell; Lee, Junghoon

2018-01-01

Respiration-induced tumor motion is a major obstacle for achieving high-precision radiotherapy of cancers in the thoracic and abdominal regions. Surrogate-based estimation and tracking methods are commonly used in radiotherapy, but with limited understanding of quantified correlation to tumor motion. In this study, we propose a method to simultaneously track the lung tumor and external surrogates to evaluate their spatial correlation in a quantitative way using dynamic MRI, which allows real-time acquisition without ionizing radiation exposure. To capture the lung and whole tumor, four MRI-compatible fiducials are placed on the patient’s chest and upper abdomen. Two different types of acquisitions are performed in the sagittal orientation including multi-slice 2D cine MRIs to reconstruct 4D-MRI and two-slice 2D cine MRIs to simultaneously track the tumor and fiducials. A phase-binned 4D-MRI is first reconstructed from multi-slice MR images using body area as a respiratory surrogate and groupwise registration. The 4D-MRI provides 3D template volumes for different breathing phases. 3D tumor position is calculated by 3D-2D template matching in which 3D tumor templates in the 4D-MRI reconstruction and the 2D cine MRIs from the two-slice tracking dataset are registered. 3D trajectories of the external surrogates are derived via matching a 3D geometrical model of the fiducials to their segmentations on the 2D cine MRIs. We tested our method on ten lung cancer patients. Using a correlation analysis, the 3D tumor trajectory demonstrates a noticeable phase mismatch and significant cycle-to-cycle motion variation, while the external surrogate was not sensitive enough to capture such variations. Additionally, there was significant phase mismatch between surrogate signals obtained from the fiducials at different locations.

A state-based probabilistic model for tumor respiratory motion prediction

NASA Astrophysics Data System (ADS)

Kalet, Alan; Sandison, George; Wu, Huanmei; Schmitz, Ruth

2010-12-01

This work proposes a new probabilistic mathematical model for predicting tumor motion and position based on a finite state representation using the natural breathing states of exhale, inhale and end of exhale. Tumor motion was broken down into linear breathing states and sequences of states. Breathing state sequences and the observables representing those sequences were analyzed using a hidden Markov model (HMM) to predict the future sequences and new observables. Velocities and other parameters were clustered using a k-means clustering algorithm to associate each state with a set of observables such that a prediction of state also enables a prediction of tumor velocity. A time average model with predictions based on average past state lengths was also computed. State sequences which are known a priori to fit the data were fed into the HMM algorithm to set a theoretical limit of the predictive power of the model. The effectiveness of the presented probabilistic model has been evaluated for gated radiation therapy based on previously tracked tumor motion in four lung cancer patients. Positional prediction accuracy is compared with actual position in terms of the overall RMS errors. Various system delays, ranging from 33 to 1000 ms, were tested. Previous studies have shown duty cycles for latencies of 33 and 200 ms at around 90% and 80%, respectively, for linear, no prediction, Kalman filter and ANN methods as averaged over multiple patients. At 1000 ms, the previously reported duty cycles range from approximately 62% (ANN) down to 34% (no prediction). Average duty cycle for the HMM method was found to be 100% and 91 ± 3% for 33 and 200 ms latency and around 40% for 1000 ms latency in three out of four breathing motion traces. RMS errors were found to be lower than linear and no prediction methods at latencies of 1000 ms. The results show that for system latencies longer than 400 ms, the time average HMM prediction outperforms linear, no prediction, and the more

Pancreatic perivascular epithelioid cell tumor: A case report with clinicopathological features and a literature review.

PubMed

Jiang, Hui; Ta, Na; Huang, Xiao-Yi; Zhang, Ming-Hua; Xu, Jing-Jing; Zheng, Kai-Lian; Jin, Gang; Zheng, Jian-Ming

2016-04-07

Perivascular epithelioid cell tumor (PEComa) of the pancreas is an unusual tumor deriving from mesenchyma. This paper described a case of pancreatic PEComa, which was initially suspected as neuroendocrine carcinoma by biopsy, and therefore surgical treatment was recommended due to undetermined diagnosis. Examination of the surgical specimen under a microscope showed that the tumor cell's morphology was epithelioid or spindle-shaped, and ranged in a nested pattern. Additionally, these cells had a large extent of acidophilic cytoplasm, no mitotic figures, and expressed HMB-45, melan-p, and smooth muscle actin immunohistochemically. Pathological examination indicated that PEComa originated from the pancreas, but symptoms related to tuberous sclerosis were absent. Since PEComa is extremely rare in the pancreas, it is likely to be ignored in differential diagnosis. In conclusion, our article highlighted the clinicopathological features of PEComa, and we conducted a literature review focusing on PEComa so as to deepen the understanding of this tumor type.

Pancreatic perivascular epithelioid cell tumor: A case report with clinicopathological features and a literature review

PubMed Central

Jiang, Hui; Ta, Na; Huang, Xiao-Yi; Zhang, Ming-Hua; Xu, Jing-Jing; Zheng, Kai-Lian; Jin, Gang; Zheng, Jian-Ming

2016-01-01

Perivascular epithelioid cell tumor (PEComa) of the pancreas is an unusual tumor deriving from mesenchyma. This paper described a case of pancreatic PEComa, which was initially suspected as neuroendocrine carcinoma by biopsy, and therefore surgical treatment was recommended due to undetermined diagnosis. Examination of the surgical specimen under a microscope showed that the tumor cell’s morphology was epithelioid or spindle-shaped, and ranged in a nested pattern. Additionally, these cells had a large extent of acidophilic cytoplasm, no mitotic figures, and expressed HMB-45, melan-p, and smooth muscle actin immunohistochemically. Pathological examination indicated that PEComa originated from the pancreas, but symptoms related to tuberous sclerosis were absent. Since PEComa is extremely rare in the pancreas, it is likely to be ignored in differential diagnosis. In conclusion, our article highlighted the clinicopathological features of PEComa, and we conducted a literature review focusing on PEComa so as to deepen the understanding of this tumor type. PMID:27053862

Strategies for early detection of resectable pancreatic cancer

PubMed Central

Okano, Keiichi; Suzuki, Yasuyuki

2014-01-01

Pancreatic cancer is difficult to diagnose at an early stage and generally has a poor prognosis. Surgical resection is the only potentially curative treatment for pancreatic carcinoma. To improve the prognosis of this disease, it is essential to detect tumors at early stages, when they are resectable. The optimal approach to screening for early pancreatic neoplasia has not been established. The International Cancer of the Pancreas Screening Consortium has recently finalized several recommendations regarding the management of patients who are at an increased risk of familial pancreatic cancer. In addition, there have been notable advances in research on serum markers, tissue markers, gene signatures, and genomic targets of pancreatic cancer. To date, however, no biomarkers have been established in the clinical setting. Advancements in imaging modalities touch all aspects of the clinical management of pancreatic diseases, including the early detection of pancreatic masses, their characterization, and evaluations of tumor resectability. This article reviews strategies for screening high-risk groups, biomarkers, and current advances in imaging modalities for the early detection of resectable pancreatic cancer. PMID:25170207

Tumor Size on Abdominal MRI Versus Pathologic Specimen in Resected Pancreatic Adenocarcinoma: Implications for Radiation Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hall, William A., E-mail: whall4@emory.edu; Winship Cancer Institute, Emory University, Atlanta, Georgia; Mikell, John L.

2013-05-01

Purpose: We assessed the accuracy of abdominal magnetic resonance imaging (MRI) for determining tumor size by comparing the preoperative contrast-enhanced T1-weighted gradient echo (3-dimensional [3D] volumetric interpolated breath-hold [VIBE]) MRI tumor size with pathologic specimen size. Methods and Materials: The records of 92 patients who had both preoperative contrast-enhanced 3D VIBE MRI images and detailed pathologic specimen measurements were available for review. Primary tumor size from the MRI was independently measured by a single diagnostic radiologist (P.M.) who was blinded to the pathology reports. Pathologic tumor measurements from gross specimens were obtained from the pathology reports. The maximum dimensions ofmore » tumor measured in any plane on the MRI and the gross specimen were compared. The median difference between the pathology sample and the MRI measurements was calculated. A paired t test was conducted to test for differences between the MRI and pathology measurements. The Pearson correlation coefficient was used to measure the association of disparity between the MRI and pathology sizes with the pathology size. Disparities relative to pathology size were also examined and tested for significance using a 1-sample t test. Results: The median patient age was 64.5 years. The primary site was pancreatic head in 81 patients, body in 4, and tail in 7. Three patients were American Joint Commission on Cancer stage IA, 7 stage IB, 21 stage IIA, 58 stage IIB, and 3 stage III. The 3D VIBE MRI underestimated tumor size by a median difference of 4 mm (range, −34-22 mm). The median largest tumor dimensions on MRI and pathology specimen were 2.65 cm (range, 1.5-9.5 cm) and 3.2 cm (range, 1.3-10 cm), respectively. Conclusions: Contrast-enhanced 3D VIBE MRI underestimates tumor size by 4 mm when compared with pathologic specimen. Advanced abdominal MRI sequences warrant further investigation for radiation therapy planning in pancreatic adenocarcinoma

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer.

PubMed

Ranjan, Alok; German, Nadezhda; Mikelis, Constantinos; Srivenugopal, Kalkunte; Srivastava, Sanjay K

2017-06-01

Pancreatic cancer is one of the most aggressive and difficult to treat cancers. Experimental and clinical evidence suggests that high basal state autophagy in pancreatic tumors could induce resistance to chemotherapy. Recently, we have demonstrated that penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis both in vitro and in vivo; however, the mechanism of autophagy induction by penfluridol was not clear. Several studies have established that endoplasmic reticulum stress could lead to autophagy and inhibit tumor progression. In this study, we demonstrated that penfluridol induced endoplasmic reticulum stress in BxPC-3, AsPC-1, and Panc-1 pancreatic cancer cell lines as indicated by upregulation of endoplasmic reticulum stress markers such as binding protein (BIP), C/EBP homologous protein (CHOP) and inositol requiring 1α (IRE1α) after treatment with penfluridol in a concentration-dependent manner. Inhibiting endoplasmic reticulum stress by pretreatment with pharmacological inhibitors such as sodium phenylbutyrate and mithramycin or by silencing CHOP using CHOP small interfering RNA, blocked penfluridol-induced autophagy. These results clearly indicate that penfluridol-induced endoplasmic reticulum stress lead to autophagy in our model. Western blot analysis of subcutaneously implanted AsPC-1 and BxPC-3 tumors as well as orthotopically implanted Panc-1 tumors demonstrated upregulation of BIP, CHOP, and IRE1α expression in the tumor lysates from penfluridol-treated mice as compared to tumors from control mice. Altogether, our study establishes that penfluridol-induced endoplasmic reticulum stress leads to autophagy resulting in reduced pancreatic tumor growth. Our study opens a new therapeutic target for advanced chemotherapies against pancreatic cancer.

Treatment Option Overview (Pancreatic Neuroendocrine Tumors / Islet Cell Tumors)

MedlinePlus

... Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

Harmonic Motion Imaging (HMI) for Tumor Imaging and Treatment Monitoring.

PubMed

Konofagou, Elisa E; Maleke, Caroline; Vappou, Jonathan

2012-01-01

Palpation is an established screening procedure for the detection of several superficial cancers including breast, thyroid, prostate, and liver tumors through both self and clinical examinations. This is because solid masses typically have distinct stiffnesses compared to the surrounding normal tissue. In this paper, the application of Harmonic Motion Imaging (HMI) for tumor detection based on its stiffness as well as its relevance in thermal treatment is reviewed. HMI uses a focused ultrasound (FUS) beam to generate an oscillatory acoustic radiation force for an internal, non-contact palpation to internally estimate relative tissue hardness. HMI studies have dealt with the measurement of the tissue dynamic motion in response to an oscillatory acoustic force at the same frequency, and have been shown feasible in simulations, phantoms, ex vivo human and bovine tissues as well as animals in vivo. Using an FUS beam, HMI can also be used in an ideal integration setting with thermal ablation using high-intensity focused ultrasound (HIFU), which also leads to an alteration in the tumor stiffness. In this paper, a short review of HMI is provided that encompasses the findings in all the aforementioned areas. The findings presented herein demonstrate that the HMI displacement can accurately depict the underlying tissue stiffness, and the HMI image of the relative stiffness could accurately detect and characterize the tumor or thermal lesion based on its distinct properties. HMI may thus constitute a non-ionizing, cost-efficient and reliable complementary method for noninvasive tumor detection, localization, diagnosis and treatment monitoring.

Harmonic Motion Imaging (HMI) for Tumor Imaging and Treatment Monitoring

PubMed Central

Maleke, Caroline; Vappou, Jonathan

2014-01-01

Palpation is an established screening procedure for the detection of several superficial cancers including breast, thyroid, prostate, and liver tumors through both self and clinical examinations. This is because solid masses typically have distinct stiffnesses compared to the surrounding normal tissue. In this paper, the application of Harmonic Motion Imaging (HMI) for tumor detection based on its stiffness as well as its relevance in thermal treatment is reviewed. HMI uses a focused ultrasound (FUS) beam to generate an oscillatory acoustic radiation force for an internal, non-contact palpation to internally estimate relative tissue hardness. HMI studies have dealt with the measurement of the tissue dynamic motion in response to an oscillatory acoustic force at the same frequency, and have been shown feasible in simulations, phantoms, ex vivo human and bovine tissues as well as animals in vivo. Using an FUS beam, HMI can also be used in an ideal integration setting with thermal ablation using high-intensity focused ultrasound (HIFU), which also leads to an alteration in the tumor stiffness. In this paper, a short review of HMI is provided that encompasses the findings in all the aforementioned areas. The findings presented herein demonstrate that the HMI displacement can accurately depict the underlying tissue stiffness, and the HMI image of the relative stiffness could accurately detect and characterize the tumor or thermal lesion based on its distinct properties. HMI may thus constitute a non-ionizing, cost-efficient and reliable complementary method for noninvasive tumor detection, localization, diagnosis and treatment monitoring. PMID:25364321

Pleiotrophin promotes perineural invasion in pancreatic cancer.

PubMed

Yao, Jun; Hu, Xiu-Feng; Feng, Xiao-Shan; Gao, She-Gan

2013-10-21

Perineural invasion (PNI) in pancreatic cancer is an important cause of local recurrence, but little is known about its mechanism. Pleiotrophin (PTN) is an important neurotrophic factor. It is of interest that our recent experimental data showed its involvement in PNI of pancreatic cancer. PTN strongly presents in the cytoplasm of pancreatic cancer cells, and high expression of PTN and its receptor may contribute to the high PNI of pancreatic cancer. Correspondingly, PNI is prone to happen in PTN-positive tumors. We thus hypothesize that, as a neurite growth-promoting factor, PTN may promote PNI in pancreatic cancer. PTN is released at the time of tumor cell necrosis, and binds with its high-affinity receptor, N-syndecan on pancreatic nerves, to promote neural growth in pancreatic cancer. Furthermore, neural destruction leads to a distorted neural homeostasis. Neurons and Schwann cells produce more N-syndecan in an effort to repair the pancreatic nerves. However, the abundance of N-syndecan attracts further PTN-positive cancer cells to the site of injury, creating a vicious cycle. Ultimately, increased PTN and N-syndecan levels, due to the continuous nerve injury, may promote cancer invasion and propagation along the neural structures. Therefore, it is meaningful to discuss the relationship between PTN/N-syndecan signaling and PNI in pancreatic cancer, which may lead to a better understanding of the mechanism of PNI in pancreatic cancer.

Pleiotrophin promotes perineural invasion in pancreatic cancer

PubMed Central

Yao, Jun; Hu, Xiu-Feng; Feng, Xiao-Shan; Gao, She-Gan

2013-01-01

Perineural invasion (PNI) in pancreatic cancer is an important cause of local recurrence, but little is known about its mechanism. Pleiotrophin (PTN) is an important neurotrophic factor. It is of interest that our recent experimental data showed its involvement in PNI of pancreatic cancer. PTN strongly presents in the cytoplasm of pancreatic cancer cells, and high expression of PTN and its receptor may contribute to the high PNI of pancreatic cancer. Correspondingly, PNI is prone to happen in PTN-positive tumors. We thus hypothesize that, as a neurite growth-promoting factor, PTN may promote PNI in pancreatic cancer. PTN is released at the time of tumor cell necrosis, and binds with its high-affinity receptor, N-syndecan on pancreatic nerves, to promote neural growth in pancreatic cancer. Furthermore, neural destruction leads to a distorted neural homeostasis. Neurons and Schwann cells produce more N-syndecan in an effort to repair the pancreatic nerves. However, the abundance of N-syndecan attracts further PTN-positive cancer cells to the site of injury, creating a vicious cycle. Ultimately, increased PTN and N-syndecan levels, due to the continuous nerve injury, may promote cancer invasion and propagation along the neural structures. Therefore, it is meaningful to discuss the relationship between PTN/N-syndecan signaling and PNI in pancreatic cancer, which may lead to a better understanding of the mechanism of PNI in pancreatic cancer. PMID:24151381

Expression of HOXB2, a retinoic acid signaling target in pancreatic cancer and pancreatic intraepithelial neoplasia.

PubMed

Segara, Davendra; Biankin, Andrew V; Kench, James G; Langusch, Catherine C; Dawson, Amanda C; Skalicky, David A; Gotley, David C; Coleman, Maxwell J; Sutherland, Robert L; Henshall, Susan M

2005-05-01

Despite significant progress in understanding the molecular pathology of pancreatic cancer and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility as prognostic or therapeutic markers. Here, we used oligonucleotide microarrays to interrogate mRNA expression of pancreatic cancer tissue and normal pancreas to identify novel molecular pathways dysregulated in the development and progression of pancreatic cancer. RNA was hybridized to Affymetrix Genechip HG-U133 oligonucleotide microarrays. A relational database integrating data from publicly available resources was created to identify candidate genes potentially relevant to pancreatic cancer. The protein expression of one candidate, homeobox B2 (HOXB2), in PanIN and pancreatic cancer was assessed using immunohistochemistry. We identified aberrant expression of several components of the retinoic acid (RA) signaling pathway (RARalpha, MUC4, Id-1, MMP9, uPAR, HB-EGF, HOXB6, and HOXB2), many of which are known to be aberrantly expressed in pancreatic cancer and PanIN. HOXB2, a downstream target of RA, was up-regulated 6.7-fold in pancreatic cancer compared with normal pancreas. Immunohistochemistry revealed ectopic expression of HOXB2 in 15% of early PanIN lesions and 48 of 128 (38%) pancreatic cancer specimens. Expression of HOXB2 was associated with nonresectable tumors and was an independent predictor of poor survival in resected tumors. We identified aberrant expression of RA signaling components in pancreatic cancer, including HOXB2, which was expressed in a proportion of PanIN lesions. Ectopic expression of HOXB2 was associated with a poor prognosis for all patients with pancreatic cancer and was an independent predictor of survival in patients who underwent resection.

Analysis of MUC4 expression in human pancreatic cancer xenografts in immunodeficient mice.

PubMed

Ansari, Daniel; Bauden, Monika P; Sasor, Agata; Gundewar, Chinmay; Andersson, Roland

2014-08-01

Mucin 4 (MUC4) is a cell surface glycoprotein that is overexpressed in most pancreatic tumors. The aim of the present study was to characterize MUC4 expression in experimental pancreatic cancer in order to clarify the correlation between MUC4 and pancreatic cancer histology in vivo. Pancreatic xenograft tumors were generated in immunodeficient mice (n=15) by subcutaneous injection of MUC4(+) human pancreatic cancer cell lines Capan-1, HPAF-II or CD18/HPAF. MUC4 immunoreactivity was compared between the cancer models. Alpha-smooth muscle actin (α-SMA) was used to identify cancer-associated fibroblasts and the amount of collagen fibers was quantified with sirius red. Tumor incidence was 100%. Tumor size showed no difference across groups (p=0.796). The median MUC4 count was highest in Capan-1 tumors (p=0.002). α-SMA and collagen extent were also highest in Capan-1 tumors (p=0.018). The Capan-1 xenograft model could serve as a valuable resource to test new therapeutic strategies targeting MUC4 in pancreatic cancer. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Outcomes analysis of laparoscopic resection of pancreatic neoplasms.

PubMed

Pierce, R A; Spitler, J A; Hawkins, W G; Strasberg, S M; Linehan, D C; Halpin, V J; Eagon, J C; Brunt, L M; Frisella, M M; Matthews, B D

2007-04-01

Experience with laparoscopic resection of pancreatic neoplasms remains limited. The purpose of this study is to critically analyze the indications for and outcomes after laparoscopic resection of pancreatic neoplasms. The medical records of all patients undergoing laparoscopic resection of pancreatic neoplasms from July 2000 to February 2006 were reviewed. Data are expressed as mean +/- standard deviation. Laparoscopic pancreatic resection was performed in 22 patients (M:F, 8:14) with a mean age of 56.3 +/- 15.1 years and mean body mass index (BMI) of 26.3 +/- 4.5 kg/m2. Nine patients had undergone previous intra-abdominal surgery. Indications for pancreatic resection were cyst (1), glucagonoma (1), gastrinoma (2), insulinoma (3), metastatic tumor (2), IPMT (4), nonfunctioning neuroendocrine tumor (3), and mucinous/serous cystadenoma (6). Mean tumor size was 2.4 +/- 1.6 cm. Laparoscopic distal pancreatectomy was attempted in 18 patients and completed in 17, and enucleation was performed in 4 patients. Laparoscopic ultrasound (n = 10) and a hand-assisted technique (n = 4) were utilized selectively. Mean operative time was 236 +/- 60 min and mean blood loss was 244 +/- 516 ml. There was one conversion to an open procedure because of bleeding from the splenic vein. The mean postoperative LOS was 4.5 +/- 2.0 days. Seven patients experienced a total of ten postoperative complications, including a urinary tract infection (UTI) (1), lower-extremity deep venous thrombosis (DVT) and pulmonary embolus (1), infected peripancreatic fluid collection (1), pancreatic pseudocyst (1), and pancreatic fistula (6). Five pancreatic fistulas were managed by percutaneous drainage. The reoperation rate was 4.5% and the overall pancreatic-related complication rate was 36.4%. One patient developed pancreatitis and a pseudocyst 5 months postoperatively, which was managed successfully with a pancreatic duct stent. There was no 30-day mortality. Laparoscopic pancreatic resection is safe and

P-HPB-21: Isolated pancreatic tuberculosis mimicking inoperable pancreatic cancer

PubMed Central

Sahu, Manoj Kumar; Singh, Ayashkanta; Behera, Debasmita; Behera, Manas; Narayan, Jimmy

2017-01-01

Background: Pancreatic tuberculosis is an uncommon disease, presenting as hypoechoic mass on imaging mimicking malignancy. Consequently, it represents a diagnostic challenge necessitating a tissue diagnosis. Case Report: A 75-year-old female presented with progressive jaundice and weight loss; imaging with computed tomography (CT) showed a large (5.8 cm × 4.6 cm) pancreatic head mass with encasement of portal and superior mesenteric veins, peripancreatic nodes, atrophic pancreatic parenchyma, and dilated main pancreatic duct. Cancer antigen 19-9 was moderately elevated. With a diagnosis of inoperable pancreatic malignancy, she was planned for tissue diagnosis and palliative chemotherapy. Endoscopic ultrasonography (EUS) showed a heterogeneous mass with vascular invasion as in the CT. Fine needle aspiration (FNA) and biliary decompression with a plastic stent performed in the same sitting. Cytology demonstrated granuloma with caseous necrosis and presence of acid-fast bacilli. Antituberculosis treatment was started, and repeat CT after 6 months showed resolution of the mass. Discussion and Conclusion: A diagnosis of isolated pancreatic tuberculosis is rare and is difficult by clinical presentation alone; in India, it should be considered as a differential diagnosis of a pancreatic tumor. Benign lesions can also present with vascular invasions mimicking inoperable malignancy. EUS FNA is a very useful tool in accurate diagnosis of pancreatic head mass avoiding unnecessary surgeries.

Differential Motion Between Mediastinal Lymph Nodes and Primary Tumor in Radically Irradiated Lung Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schaake, Eva E.; Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam; Rossi, Maddalena M.G.

2014-11-15

Purpose/Objective: In patients with locally advanced lung cancer, planning target volume margins for mediastinal lymph nodes and tumor after a correction protocol based on bony anatomy registration typically range from 1 to 1.5 cm. Detailed information about lymph node motion variability and differential motion with the primary tumor, however, is lacking from large series. In this study, lymph node and tumor position variability were analyzed in detail and correlated to the main carina to evaluate possible margin reduction. Methods and Materials: Small gold fiducial markers (0.35 × 5 mm) were placed in the mediastinal lymph nodes of 51 patients with non-small cell lung cancermore » during routine diagnostic esophageal or bronchial endoscopic ultrasonography. Four-dimensional (4D) planning computed tomographic (CT) and daily 4D cone beam (CB) CT scans were acquired before and during radical radiation therapy (66 Gy in 24 fractions). Each CBCT was registered in 3-dimensions (bony anatomy) and 4D (tumor, marker, and carina) to the planning CT scan. Subsequently, systematic and random residual misalignments of the time-averaged lymph node and tumor position relative to the bony anatomy and carina were determined. Additionally, tumor and lymph node respiratory amplitude variability was quantified. Finally, required margins were quantified by use of a recipe for dual targets. Results: Relative to the bony anatomy, systematic and random errors ranged from 0.16 to 0.32 cm for the markers and from 0.15 to 0.33 cm for the tumor, but despite similar ranges there was limited correlation (0.17-0.71) owing to differential motion. A large variability in lymph node amplitude between patients was observed, with an average motion of 0.56 cm in the cranial-caudal direction. Margins could be reduced by 10% (left-right), 27% (cranial-caudal), and 10% (anteroposterior) for the lymph nodes and −2%, 15%, and 7% for the tumor if an online carina registration protocol replaced

Dendritic Cells Promote Pancreatic Viability in Mice with Acute Pancreatitis

PubMed Central

Bedrosian, Andrea S.; Nguyen, Andrew H.; Hackman, Michael; Connolly, Michael K.; Malhotra, Ashim; Ibrahim, Junaid; Cieza-Rubio, Napoleon E.; Henning, Justin R.; Barilla, Rocky; Rehman, Adeel; Pachter, H. Leon; Medina-Zea, Marco V.; Cohen, Steven M.; Frey, Alan B.; Acehan, Devrim; Miller, George

2011-01-01

Background & Aims Acute pancreatitis increases morbidity and mortality from organ necrosis by mechanisms that are incompletely understood. Dendritic cells (DCs) can promote or suppress inflammation, depending on their subtype and context. We investigated the roles of DC in development of acute pancreatitis. Methods Acute pancreatitis was induced in CD11c.DTR mice using caerulein or L-arginine; DCs were depleted by administration of diphtheria toxin. Survival was analyzed using Kaplan-Meier analysis. Results Numbers of MHC II+CD11c+DC increased 100-fold in pancreas of mice with acute pancreatitis, to account for nearly 15% of intra-pancreatic leukocytes. Intra-pancreatic DC acquired an immune phenotype in mice with acute pancreatitis; they expressed higher levels of MHC II and CD86 and increased production of interleukin-6, membrane cofactor protein (MCP)-1, and tumor necrosis factor (TNF)-α. However, rather than inducing an organ-destructive inflammatory process, DC were required for pancreatic viability; the exocrine pancreas died in mice that were depleted of DC and challenged with caerulein or L-arginine. All mice with pancreatitis that were depleted of DC died from acinar cell death within 4 days. Depletion of DC from mice with pancreatitis resulted in neutrophil infiltration and increased levels of systemic markers of inflammation. However, the organ necrosis associated with depletion of DC did not require infiltrating neutrophils, activation of NF-κB, or signaling by mitogen-activated protein kinase or TNF-α. Conclusions DC are required for pancreatic viability in mice with acute pancreatitis and might protect organs against cell stress. PMID:21801698

ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer.

PubMed

Drosos, Yiannis; Escobar, David; Chiang, Ming-Yi; Roys, Kathryn; Valentine, Virginia; Valentine, Marc B; Rehg, Jerold E; Sahai, Vaibhav; Begley, Lesa A; Ye, Jianming; Paul, Leena; McKinnon, Peter J; Sosa-Pineda, Beatriz

2017-09-11

Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia-telangiectasia-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (Kras G12D ). We show that partial or total ATM deficiency cooperates with Kras G12D to promote highly metastatic pancreatic cancer. We also reveal that ATM is activated in pancreatic precancerous lesions in the context of DNA damage and cell proliferation, and demonstrate that ATM deficiency leads to persistent DNA damage in both precancerous lesions and primary tumors. Using low passage cultures from primary tumors and liver metastases we show that ATM loss accelerates Kras-induced carcinogenesis without conferring a specific phenotype to pancreatic tumors or changing the status of the tumor suppressors p53, p16 Ink4a and p19 Arf . However, ATM deficiency markedly increases the proportion of chromosomal alterations in pancreatic primary tumors and liver metastases. More importantly, ATM deficiency also renders murine pancreatic tumors highly sensitive to radiation. These and other findings in our study conclusively establish that ATM activity poses a major barrier to oncogenic transformation in the pancreas via maintaining genomic stability.

miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Jong-Kook; Henry, Jon C.; Jiang, Jinmai

2011-03-25

Research highlights: {yields} The expression of miR-132 and miR-212 are significantly increased in pancreatic cancer. {yields} miR-132 and miR-212 target the tumor suppressor pRb, resulting in enhanced proliferation. {yields} miR-132 and miR-212 expression is increased by a {beta}2 adrenergic receptor agonist, suggesting a novel mechanism for pancreatic cancer progression. -- Abstract: Numerous microRNAs (miRNAs) are reported as differentially expressed in cancer, however the consequence of miRNA deregulation in cancer is unknown for many miRNAs. We report that two miRNAs located on chromosome 17p13, miR-132 and miR-212, are over-expressed in pancreatic adenocarcinoma (PDAC) tissues. Both miRNAs are predicted to target themore » retinoblastoma tumor suppressor, Rb1. Validation of this interaction was confirmed by luciferase reporter assay and western blot in a pancreatic cancer cell line transfected with pre-miR-212 and pre-miR-132 oligos. Cell proliferation was enhanced in Panc-1 cells transfected with pre-miR-132/-212 oligos. Conversely, antisense oligos to miR-132/-212 reduced cell proliferation and caused a G{sub 2}/M cell cycle arrest. The mRNA of a number of E2F transcriptional targets were increased in cells over expressing miR-132/-212. Exposing Panc-1 cells to the {beta}2 adrenergic receptor agonist, terbutaline, increased the miR-132 and miR-212 expression by 2- to 4-fold. We report that over-expression of miR-132 and miR-212 result in reduced pRb protein in pancreatic cancer cells and that the increase in cell proliferation from over-expression of these miRNAs is likely due to increased expression of several E2F target genes. The {beta}2 adrenergic pathway may play an important role in this novel mechanism.« less

Cystic pancreatic neoplasms evaluation by CT and magnetic resonance cholangiopancreatography.

PubMed

Sahani, Dushyant; Prasad, Srinivasa; Saini, Sanjay; Mueller, Peter

2002-10-01

CT provides limited assistance in the differentiation between serous and mucinous neoplasms. Because of the variability in the radiographic appearance of serous cystadenomas and overlap in CT characteristics with mucinous neoplasms, most serous neoplasms still require ancillary testing such as biopsy to reach a definitive diagnosis. MRCP is useful in differentiating benign and malignant mucinous tumors including IPMT of the pancreas. The presence of mural nodules is suggestive of malignancy; however, the absence of mural nodules does not indicate that the tumor is benign. A maximum main pancreatic duct diameter of greater than 15 mm and diffuse dilatation of the main pancreatic duct are suggestive of malignancy in main duct-type tumors. Among branch duct-type tumors, malignant tumors tend to be larger than benign tumors; however, this finding is variable. The presence of main pancreatic duct dilatation may be helpful in determining malignancy of branch duct-type tumors.

Role of endoscopic ultrasound in the molecular diagnosis of pancreatic cancer

PubMed Central

Bournet, Barbara; Gayral, Marion; Torrisani, Jérôme; Selves, Janick; Cordelier, Pierre; Buscail, Louis

2014-01-01

Pancreatic ductal adenocarcinoma remains one of the most deadly types of tumor. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a safe, cost-effective, and accurate technique for evaluating and staging pancreatic tumors. However, EUS-FNA may be inconclusive or doubtful in up to 20% of cases. This review underlines the clinical interest of the molecular analysis of samples obtained by EUS-FNA in assessing diagnosis or prognosis of pancreatic cancer, especially in locally advanced tumors. On EUS-FNA materials DNA, mRNA and miRNA can be extracted, amplified, quantified and subjected to methylation assay. Kras mutation assay, improves diagnosis of pancreatic cancer. When facing to clinical and radiological presentations of pseudo-tumorous chronic pancreatitis, wild-type Kras is evocative of benignity. Conversely, in front of a pancreatic mass suspected of malignancy, a mutated Kras is highly evocative of pancreatic adenocarcinoma. This strategy can reduce false-negative diagnoses, avoids the delay of making decisions and reduces loss of surgical resectability. Similar approaches are conducted using analysis of miRNA expression as well as Mucin or markers of invasion (S100P, S100A6, PLAT or PLAU). Beyond the diagnosis approach, the prediction of response to treatment can be also investigated form biomarkers expression within EUS-FNA materials. PMID:25152579

Silencing of ATF2 inhibits growth of pancreatic cancer cells and enhances sensitivity to chemotherapy.

PubMed

Li, Mu; Wu, Xingda; Liu, Ning; Li, Xiaoying; Meng, Fanbin; Song, Shaowei

2017-06-01

Pancreatic cancer is one of the leading causes of cancer-related death worldwide. Activating transcription factor 2 (ATF2) is a multifunctional transcription factor, and is implicated in tumor progress, yet its role in pancreatic cancer remains unclear. In the present study, the level of ATF2 in pancreatic cancer tissues and the adjacent non-tumorous tissues was detected by quantitative real-time PCR and Western blot. The roles of ATF2 in the proliferation, cell cycle, and apoptosis of pancreatic cancer cells were investigated through ATF2 silencing, and the effect of ATF2 shRNA on the sensitivity of pancreatic cancer cells to gemcitabine, an anti-tumor drug, was explored. The results of our study showed that the ATF2 level in the pancreatic cancer tissues was higher than that in the adjacent non-tumorous tissues. Silencing of ATF2 was found to inhibit proliferation, arrest cell cycle at G1 phase and induce apoptosis in pancreatic cancer cells. Moreover, ATF2 silencing enhanced gemcitabine-induced growth-inhibition and apoptosis-induction effects in pancreatic cancer cells. In summary, silencing of ATF2 inhibited the growth of pancreatic cancer cells and enhanced the anti-tumor effects of gemcitabine, suggesting that ATF2 plays a pro-survival role in pancreatic cancer. Our results also propose that a high level of ATF2 may serve as a potential biomarker of pancreatic cancer, and that ATF2 may become a potential target for anti-tumor therapy. © 2017 International Federation for Cell Biology.

Role of Endogenous Cholecystokinin on Growth of Human Pancreatic Cancer

PubMed Central

Matters, Gail L.; McGovern, Christopher; Harms, John F.; Markovic, Kevin; Anson, Krystal; Jayakumar, Calpurnia; Martenis, Melissa; Awad, Christina; Smith, Jill P.

2012-01-01

Cholecystokinin (CCK) and gastrin stimulate growth of pancreatic cancer. Although down regulation of gastrin inhibits growth of pancreatic cancer, the contribution of endogenous CCK to tumor growth is unknown. The purpose of this study was to evaluate the role of endogenous CCK on autocrine growth of pancreatic cancer. Pancreatic cancer cell lines were analyzed for CCK mRNA and peptide expression by real time RT-PCR and radioimmunoassay, respectively. The effect of endogenous CCK on growth was evaluated by treating cancer cells with CCK neutralizing antibodies and by down regulating CCK mRNA by RNAi. Wild type pancreatic cancer cells expressed significantly lower CCK mRNA and peptide levels than gastrin. Neither treatment of pancreatic cancer cells with CCK antibodies nor the down regulation of CCK mRNA and peptide by shRNAs altered growth in vitro or in vivo. Conversely, when gastrin mRNA expression was down regulated, the same cells failed to produce tumors in spite of having sustained levels of endogenous CCK. Pancreatic cancer cells produce CCK and gastrin; however, the autocrine production of gastrin is more important for stimulating tumor growth. PMID:21186400

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD.

PubMed

Cortez, Eliane; Gladh, Hanna; Braun, Sebastian; Bocci, Matteo; Cordero, Eugenia; Björkström, Niklas K; Miyazaki, Hideki; Michael, Iacovos P; Eriksson, Ulf; Folestad, Erika; Pietras, Kristian

2016-02-16

Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

PubMed Central

Cortez, Eliane; Gladh, Hanna; Braun, Sebastian; Bocci, Matteo; Cordero, Eugenia; Björkström, Niklas K.; Miyazaki, Hideki; Michael, Iacovos P.; Eriksson, Ulf; Folestad, Erika; Pietras, Kristian

2016-01-01

Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis. PMID:26831065

Dosimetric evaluation of intrafractional tumor motion by means of a robot driven phantom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richter, Anne; Wilbert, Juergen; Flentje, Michael

2011-10-15

Purpose: The aim of the work was to investigate the influence of intrafractional tumor motion to the accumulated (absorbed) dose. The accumulated dose was determined by means of calculations and measurements with a robot driven motion phantom. Methods: Different motion scenarios and compensation techniques were realized in a phantom study to investigate the influence of motion on image acquisition, dose calculation, and dose measurement. The influence of motion on the accumulated dose was calculated by employing two methods (a model based and a voxel based method). Results: Tumor motion resulted in a blurring of steep dose gradients and a reductionmore » of dose at the periphery of the target. A systematic variation of motion parameters allowed the determination of the main influence parameters on the accumulated dose. The key parameters with the greatest influence on dose were the mean amplitude and the pattern of motion. Investigations on necessary safety margins to compensate for dose reduction have shown that smaller safety margins are sufficient, if the developed concept with optimized margins (OPT concept) was used instead of the standard internal target volume (ITV) concept. Both calculation methods were a reasonable approximation of the measured dose with the voxel based method being in better agreement with the measurements. Conclusions: Further evaluation of available systems and algorithms for dose accumulation are needed to create guidelines for the verification of the accumulated dose.« less

Glypican-1 is enriched in circulating-exosomes in pancreatic cancer and correlates with tumor burden.

PubMed

Frampton, Adam E; Prado, Mireia Mato; López-Jiménez, Elena; Fajardo-Puerta, Ana Belen; Jawad, Zaynab A R; Lawton, Phillip; Giovannetti, Elisa; Habib, Nagy A; Castellano, Leandro; Stebbing, Justin; Krell, Jonathan; Jiao, Long R

2018-04-10

Glypican-1 (GPC1) is expressed in pancreatic ductal adenocarcinoma (PDAC) cells and adjacent stromal fibroblasts. Recently, GPC1 circulating exosomes (crExos) have been shown to be able to detect early stages of PDAC. In this study, we investigated the usefulness of crExos GPC1 as a biomarker for PDAC. Plasma was obtained from patients with benign pancreatic disease ( n = 16) and PDAC ( n = 27) prior to pancreatectomy, and crExos were isolated by ultra-centrifugation. Protein was extracted from surgical specimens (adjacent normal pancreas, n = 13; and PDAC, n = 17). GPC1 levels were measured using enzyme-linked immunosorbent assay (ELISA). There was no significant difference in GPC1 levels between normal pancreas and PDAC tissues. This was also true when comparing matched pairs. However, GPC1 levels were enriched in PDAC crExos ( n = 11), compared to the source tumors ( n = 11; 97 ± 54 vs. 20.9 ± 12.3 pg/mL; P < 0.001). In addition, PDACs with high GPC1 expression tended to have crExos with higher GPC1 levels. Despite these findings, we were unable to distinguish PDAC from benign pancreatic disease using crExos GPC1 levels. Interestingly, we found that in matched pre and post-operative plasma samples there was a significant drop in crExos GPC1 levels after surgical resection for PDAC ( n = 11 vs. 11; 97 ± 54 vs. 77.8 ± 32.4 pg/mL; P = 0.0428). Furthermore, we found that patients with high crExos GPC1 levels have significantly larger PDACs (>4 cm; P = 0.012). High GPC1 crExos may be able to determine PDAC tumor size and disease burden. However, further efforts are needed to elucidate its role as a diagnostic and/or prognostic biomarker using larger cohorts of PDAC patients.

Capture, Release and Culture of Circulating Tumor Cells from Pancreatic Cancer Patients using an Enhanced Mixing Chip

PubMed Central

Sheng, Weian; Ogunwobi, Olorunseun O.; Chen, Tao; Zhang, Jinling; George, Thomas J.; Liu, Chen; Fan, Z. Hugh

2013-01-01

Circulating tumor cells (CTCs) from peripheral blood hold important information for cancer diagnosis and disease monitoring. Analysis of this “liquid biopsy” holds the promise to usher in a new era of personalized therapeutic treatments and real-time monitoring for cancer patients. But the extreme rarity of CTCs in blood makes their isolation and characterization technologically challenging. This paper reports the development of a geometrically enhanced mixing (GEM) chip for high-efficiency and high-purity tumor cell capture. We also successfully demonstrated the release and culture of the captured tumor cells, as well as the isolation of CTCs from cancer patients. The high-performance microchip is based on geometrically optimized micromixer structures, which enhance the transverse flow and flow folding, maximizing the interaction between CTCs and antibody-coated surfaces. With the optimized channel geometry and flow rate, the capture efficiency reached >90% with a purity of >84% when capturing spiked tumor cells in buffer. The system was further validated by isolating a wide range of spiked tumor cells (50–50,000) in 1 mL of lysed blood and whole blood. With the combination of trypsinization and high flow rate washing, captured tumor cells were efficiently released. The released cells were viable and able to proliferate, and showed no difference compared with intact cells that were not subjected to the capture and release process. Furthermore, we applied the device for detecting CTCs from metastatic pancreatic cancer patients’ blood; and CTCs were found from 17 out of 18 samples (>94%). We also tested the potential utility of the device in monitoring the response to anti-cancer drug treatment in pancreatic cancer patients, and the CTC numbers correlated with the clinical computed tomograms (CT scans) of tumors. The presented technology shows great promise for accurate CTC enumeration, biological studies of CTCs and cancer metastasis, as well as for cancer

Characterizing spatiotemporal information loss in sparse-sampling-based dynamic MRI for monitoring respiration-induced tumor motion in radiotherapy.

PubMed

Arai, Tatsuya J; Nofiele, Joris; Madhuranthakam, Ananth J; Yuan, Qing; Pedrosa, Ivan; Chopra, Rajiv; Sawant, Amit

2016-06-01

Sparse-sampling and reconstruction techniques represent an attractive strategy to achieve faster image acquisition speeds, while maintaining adequate spatial resolution and signal-to-noise ratio in rapid magnetic resonance imaging (MRI). The authors investigate the use of one such sequence, broad-use linear acquisition speed-up technique (k-t BLAST) in monitoring tumor motion for thoracic and abdominal radiotherapy and examine the potential trade-off between increased sparsification (to increase imaging speed) and the potential loss of "true" information due to greater reliance on a priori information. Lung tumor motion trajectories in the superior-inferior direction, previously recorded from ten lung cancer patients, were replayed using a motion phantom module driven by an MRI-compatible motion platform. Eppendorf test tubes filled with water which serve as fiducial markers were placed in the phantom. The modeled rigid and deformable motions were collected in a coronal image slice using balanced fast field echo in conjunction with k-t BLAST. Root mean square (RMS) error was used as a metric of spatial accuracy as measured trajectories were compared to input data. The loss of spatial information was characterized for progressively increasing acceleration factor from 1 to 16; the resultant sampling frequency was increased approximately from 2.5 to 19 Hz when the principal direction of the motion was set along frequency encoding direction. In addition to the phantom study, respiration-induced tumor motions were captured from two patients (kidney tumor and lung tumor) at 13 Hz over 49 s to demonstrate the impact of high speed motion monitoring over multiple breathing cycles. For each subject, the authors compared the tumor centroid trajectory as well as the deformable motion during free breathing. In the rigid and deformable phantom studies, the RMS error of target tracking at the acquisition speed of 19 Hz was approximately 0.3-0.4 mm, which was smaller than the

Hypermutation In Pancreatic Cancer.

PubMed

Humphris, Jeremy L; Patch, Ann-Marie; Nones, Katia; Bailey, Peter J; Johns, Amber L; McKay, Skye; Chang, David K; Miller, David K; Pajic, Marina; Kassahn, Karin S; Quinn, Michael C J; Bruxner, Timothy J C; Christ, Angelika N; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Stone, Andrew; Wilson, Peter J; Anderson, Matthew; Fink, J Lynn; Holmes, Oliver; Kazakoff, Stephen; Leonard, Conrad; Newell, Felicity; Waddell, Nick; Wood, Scott; Mead, Ronald S; Xu, Qinying; Wu, Jianmin; Pinese, Mark; Cowley, Mark J; Jones, Marc D; Nagrial, Adnan M; Chin, Venessa T; Chantrill, Lorraine A; Mawson, Amanda; Chou, Angela; Scarlett, Christopher J; Pinho, Andreia V; Rooman, Ilse; Giry-Laterriere, Marc; Samra, Jaswinder S; Kench, James G; Merrett, Neil D; Toon, Christopher W; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Jamieson, Nigel B; McKay, Colin J; Carter, C Ross; Dickson, Euan J; Graham, Janet S; Duthie, Fraser; Oien, Karin; Hair, Jane; Morton, Jennifer P; Sansom, Owen J; Grützmann, Robert; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Schulick, Richard D; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Rusev, Borislav; Corbo, Vincenzo; Salvia, Roberto; Cataldo, Ivana; Tortora, Giampaolo; Tempero, Margaret A; Hofmann, Oliver; Eshleman, James R; Pilarsky, Christian; Scarpa, Aldo; Musgrove, Elizabeth A; Gill, Anthony J; Pearson, John V; Grimmond, Sean M; Waddell, Nicola; Biankin, Andrew V

2017-01-01

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Curcumin Modulates Pancreatic Adenocarcinoma Cell-Derived Exosomal Function

PubMed Central

Osterman, Carlos J. Diaz; Lynch, James C.; Leaf, Patrick; Gonda, Amber; Ferguson Bennit, Heather R.; Griffiths, Duncan; Wall, Nathan R.

2015-01-01

Pancreatic cancer has the highest mortality rates of all cancer types. One potential explanation for the aggressiveness of this disease is that cancer cells have been found to communicate with one another using membrane-bound vesicles known as exosomes. These exosomes carry pro-survival molecules and increase the proliferation, survival, and metastatic potential of recipient cells, suggesting that tumor-derived exosomes are powerful drivers of tumor progression. Thus, to successfully address and eradicate pancreatic cancer, it is imperative to develop therapeutic strategies that neutralize cancer cells and exosomes simultaneously. Curcumin, a turmeric root derivative, has been shown to have potent anti-cancer and anti-inflammatory effects in vitro and in vivo. Recent studies have suggested that exosomal curcumin exerts anti-inflammatory properties on recipient cells. However, curcumin’s effects on exosomal pro-tumor function have yet to be determined. We hypothesize that curcumin will alter the pro-survival role of exosomes from pancreatic cancer cells toward a pro-death role, resulting in reduced cell viability of recipient pancreatic cancer cells. The main objective of this study was to determine the functional alterations of exosomes released by pancreatic cancer cells exposed to curcumin compared to exosomes from untreated pancreatic cancer cells. We demonstrate, using an in vitro cell culture model involving pancreatic adenocarcinoma cell lines PANC-1 and MIA PaCa-2, that curcumin is incorporated into exosomes isolated from curcumin-treated pancreatic cancer cells as observed by spectral studies and fluorescence microscopy. Furthermore, curcumin is delivered to recipient pancreatic cancer cells via exosomes, promoting cytotoxicity as demonstrated by Hoffman modulation contrast microscopy as well as AlamarBlue and Trypan blue exclusion assays. Collectively, these data suggest that the efficacy of curcumin may be enhanced in pancreatic cancer cells through

Pancreatic cancer: Advances in treatment

PubMed Central

Mohammed, Somala; Van Buren II, George; Fisher, William E

2014-01-01

Pancreatic cancer is a leading cause of cancer mortality and the incidence of this disease is expected to continue increasing. While patients with pancreatic cancer have traditionally faced a dismal prognosis, over the past several years various advances in diagnosis and treatment have begun to positively impact this disease. Identification of effective combinations of existing chemotherapeutic agents, such as the FOLFIRINOX and the gemcitabine + nab-paclitaxel regimen, has improved survival for selected patients although concerns regarding their toxicity profiles remain. A better understanding of pancreatic carcinogenesis has identified several pre-malignant precursor lesions, such as pancreatic intraepithelial neoplasias, intraductal papillary mucinous neoplasms, and cystic neoplasms. Imaging technology has also evolved dramatically so as to allow early detection of these lesions and thereby facilitate earlier management. Surgery remains a cornerstone of treatment for patients with resectable pancreatic tumors, and advances in surgical technique have allowed patients to undergo resection with decreasing perioperative morbidity and mortality. Surgery has also become feasible in selected patients with borderline resectable tumors as a result of neoadjuvant therapy. Furthermore, pancreatectomy involving vascular reconstruction and pancreatectomy with minimally invasive techniques have demonstrated safety without significantly compromising oncologic outcomes. Lastly, a deeper understanding of molecular aberrations contributing to the development of pancreatic cancer shows promise for future development of more targeted and safe therapeutic agents. PMID:25071330

Pancreatic cancer: advances in treatment.

PubMed

Mohammed, Somala; Van Buren, George; Fisher, William E

2014-07-28

Pancreatic cancer is a leading cause of cancer mortality and the incidence of this disease is expected to continue increasing. While patients with pancreatic cancer have traditionally faced a dismal prognosis, over the past several years various advances in diagnosis and treatment have begun to positively impact this disease. Identification of effective combinations of existing chemotherapeutic agents, such as the FOLFIRINOX and the gemcitabine + nab-paclitaxel regimen, has improved survival for selected patients although concerns regarding their toxicity profiles remain. A better understanding of pancreatic carcinogenesis has identified several pre-malignant precursor lesions, such as pancreatic intraepithelial neoplasias, intraductal papillary mucinous neoplasms, and cystic neoplasms. Imaging technology has also evolved dramatically so as to allow early detection of these lesions and thereby facilitate earlier management. Surgery remains a cornerstone of treatment for patients with resectable pancreatic tumors, and advances in surgical technique have allowed patients to undergo resection with decreasing perioperative morbidity and mortality. Surgery has also become feasible in selected patients with borderline resectable tumors as a result of neoadjuvant therapy. Furthermore, pancreatectomy involving vascular reconstruction and pancreatectomy with minimally invasive techniques have demonstrated safety without significantly compromising oncologic outcomes. Lastly, a deeper understanding of molecular aberrations contributing to the development of pancreatic cancer shows promise for future development of more targeted and safe therapeutic agents.

Pathology and Molecular Genetics of Pancreatic Neoplasms

PubMed Central

Wood, Laura D.; Hruban, Ralph H.

2014-01-01

Cancer is fundamentally a genetic disease caused by the ac cumulation of somatic mutations in oncogenes and tumor suppressor genes. In the last decade, rapid advances in sequencing and bioinformatic technology led to an explosion in sequencing studies of cancer genomes, greatly expanding our knowledge of the genetic changes underlying a variety of tumor types. Several of these studies of cancer genomes have focused on pancreatic neoplasms, and cancers from the pancreas are some of the best characterized tumors at the genetic level. Pancreatic neoplasms encompass a wide array of clinical diseases, from benign cysts to deadly cancers, and the genetic alterations underlying neoplasms of the pancreas are similarly diverse. This new knowledge of pancreatic cancer genomes has deepened our understanding of tumorigenesis in the pancreas and has opened several promising new avenues for novel diagnostics and therapeutics. PMID:23187835

Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma.

PubMed

Funamizu, Naotake; Hu, Chaoxin; Lacy, Curtis; Schetter, Aaron; Zhang, Geng; He, Peijun; Gaedcke, Jochen; Ghadimi, Michael B; Ried, Thomas; Yfantis, Harris G; Lee, Dong H; Subleski, Jeffrey; Chan, Tim; Weiss, Jonathan M; Back, Timothy C; Yanaga, Katsuhiko; Hanna, Nader; Alexander, H Richard; Maitra, Anirban; Hussain, S Perwez

2013-02-15

MIF is a proinflammatory cytokine and is implicated in cancer. A higher MIF level is found in many human cancer and cancer-prone inflammatory diseases, including chronic pancreatitis and pancreatic cancer. We tested the hypothesis that MIF contributes to pancreatic cancer aggressiveness and predicts disease outcome in resected cases. Consistent with our hypothesis we found that an elevated MIF mRNA expression in tumors was significantly associated with poor outcome in resected cases. Multivariate Cox-regression analysis further showed that MIF is independently associated with patients' survival (HR = 2.26, 95% CI = 1.17-4.37, p = 0.015). Mechanistic analyses revealed that MIF overexpression decreased E-cadherin and increased vimentin mRNA and protein levels in pancreatic cancer cell lines, consistent with the features of epithelial-to-mesenchymal transition (EMT). Furthermore, MIF-overexpression significantly increased ZEB1/2 and decreased miR-200b expression, while shRNA-mediated inhibition of MIF increased E-cadherin and miR-200b expression, and reduced the expression of ZEB1/2 in Panc1 cells. Re-expression of miR-200b in MIF overexpressing cells restored the epithelial characteristics, as indicated by an increase in E-cadherin and decrease in ZEB1/2 and vimentin expression. A reduced sensitivity to the chemotherapeutic drug, gemcitabine, occurred in MIF-overexpressing cells. Indicative of an increased malignant potential, MIF over-expressing cells showed significant increase in their invasion ability in vitro, and tumor growth and metastasis in an orthotopic xenograft mouse model. These results support a role of MIF in disease aggressiveness, indicating its potential usefulness as a candidate target for designing improved treatment in pancreatic cancer. Copyright © 2012 UICC.

Solitary pancreatic head metastasis from tibial adamantinoma: a rare indication to pancreaticoduodenectomy

PubMed Central

Silvestri, S; Sandrucci, S; Comandone, A; Molinaro, L; Chiusa, L; Fronda, G R; Franchello, A

2018-01-01

Abstract Pancreatic metastases are rare, <2% of all pancreatic neoplasia. This is the first case of pancreatic metastasis from adamantinoma, a rare, low grade and slow growing tumor which is frequently localized in long bones. We describe a case of a 45-year-old woman presenting with increased bilirubin level. Computed tomography and ecoendoscopic ultra sonography revealed a pancreatic head mass. Fine-needle aspiration biopsy was consistent with metastatic adamantinoma. The patient was submitted to a standard pancreaticoduodenectomy. As in the case presented, standard pancreatic resections are safe and feasible options to treat non-pancreatic primary tumor improving patient’s survival and quality of life. PMID:29479415

TGF-β in pancreatic cancer initiation and progression: two sides of the same coin.

PubMed

Shen, Wei; Tao, Guo-Qing; Zhang, Yu; Cai, Bing; Sun, Jian; Tian, Zhi-Qiang

2017-01-01

Pancreatic cancer is highly lethal malignant tumor with characterised rapid progression, invasiveness and resistance to radiochemotherapy. Transforming growth factor-β (TGF-β) signaling plays a dual role in both pro-tumorigenic and tumor suppressive of pancreatic cancer, depending on tumor stage and microenvironment. TGF-β signaling components alteration are common in pancreatic cancer, and its leading role in tumor formation and metastases has received increased attention. Many therapies have investigated to target TGF-β signaling in the preclinical and clinical setting. In this review, we highlight the dual roles of TGF-β and touch upon the perspectives on therapeutic target of TGF-β signaling in pancreatic cancer.

Local pressure and matrix component effects on verteporfin distribution in pancreatic tumors (Conference Presentation)

NASA Astrophysics Data System (ADS)

Nieskoski, Michael D.; Marra, Kayla; Gunn, Jason R.; Doyley, Marvin; Samkoe, Kimberly S.; Pereira, Stephen P.; Trembly, B. Stuart; Pogue, Brian W.

2017-02-01

Pancreatic tumors are characterized by large interstitial hypertension from enhanced deposition of extracellular matrix components, resulting in widespread vascular collapse and reduced molecular uptake of systemically delivered therapies. Although the origins of hypoperfusion is debated amongst researchers, spatial distribution of collagen density and hyaluronic acid content have shown to be a key metric in understanding the lack of efficacy for both acute and chronic therapies in these tumors. In this study, the AsPC-1 tumor model was used both subcutaneously and orthotopically to study the measurable factors which are related to this. A conventional piezoelectric pressure catheter was used to measure total tissue pressure (TTP), defined as a combination of solid stress (SS) and interstitial fluid pressure (IFP), TTP = SS + IFP, in multiple locations within the tumor interstitium. Matrix components such as collagen and hyaluronic acid were scored using masson's trichrome stain and hyaluronic acid binding protein (HABP), respectively, and co-registered with values of TTP. The results show that these key measurements are related to the spatial distribution of verteporfin in the same tumors. Photodynamic treatment with verteporfin is known to ablate large regions of tumor tissue and also allow better permeability for chemotherapies. The study of spatial distribution of verteporfin in relation to stromal content and TTP will help us better control these types of combination therapies.

Pretreatment Carbohydrate Antigen 19-9 Level Indicates Tumor Response, Early Distant Metastasis, Overall Survival, and Therapeutic Selection in Localized and Unresectable Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yoo, Tae; Lee, Woo Jin; Woo, Sang Myung

2011-11-15

Purpose: The use of chemoradiotherapy (CRT) for localized and unresectable pancreatic cancer has been disputed because of high probability of distant metastasis. Thus, we analyzed the effect of clinical parameters on tumor response, early distant metastasis within 3 months (DM{sup 3m}), and overall survival to identify an indicator for selecting patients who would benefit from CRT. Methods and Materials: This study retrospectively analyzed the data from 84 patients with localized and unresectable pancreatic cancer who underwent CRT between August 2002 and October 2009. Sex, age, tumor size, histological differentiation, N classification, pre- and post-treatment carbohydrate antigen (CA) 19-9 level, andmore » CA 19-9 percent decrease were analyzed to identify risk factors associated with tumor response, DM{sup 3m}, and overall survival. Results: For all 84 patients, the median survival time was 12.5 months (range, 2-31.9 months), objective response (complete response or partial response) to CRT was observed in 28 patients (33.3%), and DM{sup 3m} occurred in 24 patients (28.6%). Multivariate analysis showed that pretreatment CA 19-9 level ({<=}400 vs. >400 U/ml) was significantly associated with tumor response (45.1% vs. 15.2%), DM{sup 3m} (19.6% vs. 42.4%), and median overall survival time (15.1 vs. 9.7 months) (p < 0.05 for all three parameters). Conclusion: For patients with localized and unresectable pancreatic cancer, pretreatment CA 19-9 level could be helpful in predicting tumor response, DM{sup 3m}, and overall survival and identifying patients who will benefit from CRT.« less

Treatment Options for Pancreatic Neuroendocrine Tumors

MedlinePlus

... Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

TH-EF-BRA-04: Individually Optimized Contrast-Enhanced 4D-CT for Radiotherapy Simulation in Pancreatic Ductal Adenocarcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, W; Xue, M; Lane, B

Purpose: To develop an individually optimized contrast-enhanced (CE) 4D-CT for radiotherapy simulation in pancreatic ductal adenocarcinomas (PDA). Methods: Ten PDA patients were enrolled. Each underwent 3 CT scans: a 4D-CT immediately following a CE 3D-CT and an individually optimized CE 4D-CT using test injection. Three physicians contoured the tumor and pancreatic tissues. We compared image quality scores, tumor volume, motion, tumor-to-pancreas contrast, and contrast-to-noise ratio (CNR) in the 3 CTs. We also evaluated interobserver variations in contouring the tumor using simultaneous truth and performance level estimation (STAPLE). Results: Average image quality scores for CE 3DCT and CE 4D-CT were comparablemore » (4.0 and 3.8, respectively; P=0.47), and both were significantly better than that for 4D-CT (2.6, P<0.001). Tumor-to-pancreas contrast results were comparable in CE 3D-CT and CE 4D-CT (15.5 and 16.7 HU, respectively; P=0.71), and the latter was significantly higher than in 4D-CT (9.2 HU, P=0.03). Image noise in CE 3D-CT (12.5 HU) was significantly lower than in CE 4D-CT (22.1 HU, P<0.001) and 4D-CT (19.4 HU, P=0.005). CNRs were comparable in CE 3D-CT and CE 4DCT (1.4 and 0.8, respectively; P=0.23), and the former was significantly better than in 4D-CT (0.6, P = 0.04). Mean tumor volumes were smaller in CE 3D-CT (29.8 cm{sup 3}) and CE 4D-CT (22.8 cm{sup 3}) than in 4D-CT (42.0 cm{sup 3}), although these differences were not statistically significant. Mean tumor motion was comparable in 4D-CT and CE 4D-CT (7.2 and 6.2 mm, P=0.23). Interobserver variations were comparable in CE 3D-CT and CE 4D-CT (Jaccard index 66.0% and 61.9%, respectively) and were worse for 4D-CT (55.6%) than CE 3D-CT. Conclusion: CE 4D-CT demonstrated characteristics comparable to CE 3D-CT, with high potential for simultaneously delineating the tumor and quantifying tumor motion with a single scan. Supported in part by Philips Healthcare.« less

[Advance in the biology of pancreatic of cancer].

PubMed

Buscail, Louis; Bournet, Barbara; Dufresne, Marlène; Torrisani, Jérôme; Cordelier, Pierre

2015-06-01

The understanding of the biology of pancreatic carcinoma has greatly benefited from studies of genetic/epigenetic alterations and molecular expression in experimental models as well as precancerous and cancerous tissues by mean of molecular amplification and large-scale transcriptoma analysis. P16, TP53, DPC4/Smad4 tumor suppressor pathways are genetically inactivated in the majority of pancreatic carcinomas, whereas oncogenic k-ras is activated. The activating point mutation of the KRAS oncogene on codon 12 is the major event and occurs early in pancreatic carcinogenesis. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, Nerve Growth Factor, gastrin), of pro-angiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, tissue plasminogen activators) occurs. The microenvironment plays also a key role in the invasive and metastatic process of pancreatic carcinoma with a strong relationship between cancerous cells and pancreatic stellate cells as well as extracellular matrix. This microenvironment strongly participates to the tumor fibrosis, hypoxia and hypovascularization inducing an inaccessibility of drugs. Nowadays, the targeting of microenvironment takes a special place in the new therapeutic strategies of pancreatic cancer in combination with chemotherapy. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

Characterizing spatiotemporal information loss in sparse-sampling-based dynamic MRI for monitoring respiration-induced tumor motion in radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arai, Tatsuya J.; Nofiele, Joris; Yuan, Qing

Purpose: Sparse-sampling and reconstruction techniques represent an attractive strategy to achieve faster image acquisition speeds, while maintaining adequate spatial resolution and signal-to-noise ratio in rapid magnetic resonance imaging (MRI). The authors investigate the use of one such sequence, broad-use linear acquisition speed-up technique (k-t BLAST) in monitoring tumor motion for thoracic and abdominal radiotherapy and examine the potential trade-off between increased sparsification (to increase imaging speed) and the potential loss of “true” information due to greater reliance on a priori information. Methods: Lung tumor motion trajectories in the superior–inferior direction, previously recorded from ten lung cancer patients, were replayed usingmore » a motion phantom module driven by an MRI-compatible motion platform. Eppendorf test tubes filled with water which serve as fiducial markers were placed in the phantom. The modeled rigid and deformable motions were collected in a coronal image slice using balanced fast field echo in conjunction with k-t BLAST. Root mean square (RMS) error was used as a metric of spatial accuracy as measured trajectories were compared to input data. The loss of spatial information was characterized for progressively increasing acceleration factor from 1 to 16; the resultant sampling frequency was increased approximately from 2.5 to 19 Hz when the principal direction of the motion was set along frequency encoding direction. In addition to the phantom study, respiration-induced tumor motions were captured from two patients (kidney tumor and lung tumor) at 13 Hz over 49 s to demonstrate the impact of high speed motion monitoring over multiple breathing cycles. For each subject, the authors compared the tumor centroid trajectory as well as the deformable motion during free breathing. Results: In the rigid and deformable phantom studies, the RMS error of target tracking at the acquisition speed of 19 Hz was approximately 0

Characterizing spatiotemporal information loss in sparse-sampling-based dynamic MRI for monitoring respiration-induced tumor motion in radiotherapy

PubMed Central

Arai, Tatsuya J.; Nofiele, Joris; Madhuranthakam, Ananth J.; Yuan, Qing; Pedrosa, Ivan; Chopra, Rajiv; Sawant, Amit

2016-01-01

Purpose: Sparse-sampling and reconstruction techniques represent an attractive strategy to achieve faster image acquisition speeds, while maintaining adequate spatial resolution and signal-to-noise ratio in rapid magnetic resonance imaging (MRI). The authors investigate the use of one such sequence, broad-use linear acquisition speed-up technique (k-t BLAST) in monitoring tumor motion for thoracic and abdominal radiotherapy and examine the potential trade-off between increased sparsification (to increase imaging speed) and the potential loss of “true” information due to greater reliance on a priori information. Methods: Lung tumor motion trajectories in the superior–inferior direction, previously recorded from ten lung cancer patients, were replayed using a motion phantom module driven by an MRI-compatible motion platform. Eppendorf test tubes filled with water which serve as fiducial markers were placed in the phantom. The modeled rigid and deformable motions were collected in a coronal image slice using balanced fast field echo in conjunction with k-t BLAST. Root mean square (RMS) error was used as a metric of spatial accuracy as measured trajectories were compared to input data. The loss of spatial information was characterized for progressively increasing acceleration factor from 1 to 16; the resultant sampling frequency was increased approximately from 2.5 to 19 Hz when the principal direction of the motion was set along frequency encoding direction. In addition to the phantom study, respiration-induced tumor motions were captured from two patients (kidney tumor and lung tumor) at 13 Hz over 49 s to demonstrate the impact of high speed motion monitoring over multiple breathing cycles. For each subject, the authors compared the tumor centroid trajectory as well as the deformable motion during free breathing. Results: In the rigid and deformable phantom studies, the RMS error of target tracking at the acquisition speed of 19 Hz was approximately 0.3–0

Biodistribution and Pharmacokinetics of EGFR-Targeted Thiolated Gelatin Nanoparticles Following Systemic Administration in Pancreatic Tumor-Bearing Mice

PubMed Central

Xu, Jing; Gattacceca, Florence; Amiji, Mansoor

2013-01-01

The objective of this study was to evaluate qualitative and quantitative biodistribution of epidermal growth factor receptor (EGFR)-targeted thiolated type B gelatin nanoparticles in vivo in a subcutaneous human pancreatic adenocarcinoma (Panc-1) bearing female SCID Beige mice. EGFR-targeted nanoparticles showed preferential and sustained accumulation in the tumor mass, especially at early time points. Higher blood concentrations and higher tumor accumulations were observed with PEG-modified and EGFR-targeted nanoparticles during the study (AUClast: 17.38 and 19.56 %ID/mL*h in blood, 187 and 322 %ID/g*h in tumor for PEG-modified and EGFR-targeted nanoparticles, respectively), as compared to control, unmodified particles (AUClast: 10.71 %ID/mL*h in blood and 138 %ID/g*h in tumor). EGFR-targeted nanoparticles displayed almost twice tumor targeting efficiency than either PEG-modified or the unmodified nanoparticles, highlighting the efficacy of the active targeting strategy. In conclusion, this study shows that EGFR-targeted and PEG-modified nanoparticles were suitable vehicles for specific systemic delivery in subcutaneous Panc-1 tumor xenograft models. PMID:23544877

Biodistribution and pharmacokinetics of EGFR-targeted thiolated gelatin nanoparticles following systemic administration in pancreatic tumor-bearing mice.

PubMed

Xu, Jing; Gattacceca, Florence; Amiji, Mansoor

2013-05-06

The objective of this study was to evaluate qualitative and quantitative biodistribution of epidermal growth factor receptor (EGFR)-targeted thiolated type B gelatin nanoparticles in vivo in subcutaneous human pancreatic adenocarcinoma (Panc-1) bearing female SCID Beige mice. EGFR-targeted nanoparticles showed preferential and sustained accumulation in the tumor mass, especially at early time points. Higher blood concentrations and higher tumor accumulations were observed with PEG-modified and EGFR-targeted nanoparticles during the study (AUClast: 17.38 and 19.56%ID/mL·h in blood, 187 and 322%ID/g·h in tumor for PEG-modified and EGFR-targeted nanoparticles, respectively), as compared to control, unmodified particles (AUClast: 10.71%ID/mL·h in blood and 138%ID/g·h in tumor). EGFR-targeted nanoparticles displayed almost twice tumor targeting efficiency than either PEG-modified or the unmodified nanoparticles, highlighting the efficacy of the active targeting strategy. In conclusion, this study shows that EGFR-targeted and PEG-modified nanoparticles were suitable vehicles for specific systemic delivery in subcutaneous Panc-1 tumor xenograft models.

A Novel Microfluidic Device for Isolation of Circulating Tumor Cells from Pancreatic Cancer Blood Samples.

PubMed

Varillas, Jose I; Chen, Kangfu; Zhang, Jinling; George, Thomas J; Hugh Fan, Z

2017-01-01

Enumeration of circulating tumor cells (CTCs) can provide valuable prognostic information to guide cancer treatment as well as help monitor disease progression. Analysis of these rare malignant cells has the potential to further our understanding of cancer metastasis by gaining insights into CTC characteristics and properties. Microfluidics presents a unique platform to isolate and study CTCs. In this chapter, we describe the detailed procedures for the fabrication and use of a microfluidic device to detect CTCs from the blood of pancreatic cancer patients.

The miR-24-Bim pathway promotes tumor growth and angiogenesis in pancreatic carcinoma.

PubMed

Liu, Rui; Zhang, Haiyang; Wang, Xia; Zhou, Likun; Li, Hongli; Deng, Ting; Qu, Yanjun; Duan, Jingjing; Bai, Ming; Ge, Shaohua; Ning, Tao; Zhang, Le; Huang, Dingzhi; Ba, Yi

2015-12-22

miRNAs are a group of small RNAs that have been reported to play a key role at each stage of tumorigenesis and are believed to have future practical value. We now demonstrate that Bim, which stimulates cell apoptosis, is obviously down-regulated in pancreatic cancer (PaC) tissues and cell lines. And Bim-related miR-24 is significantly up-regulated in PaC. The repressed expression of Bim is proved to be a result of miR-24, thus promoting cell growth of both cancer and vascular cells, and accelerating vascular ring formation. By using mouse tumor model, we clearly showed that miR-24 promotes tumor growth and angiogenesis by suppressing Bim expression in vivo. Therefore, a new pathway comprising miR-24 and Bim can be used in the exploration of drug-target therapy of PaC.

Robustness of external/internal correlation models for real-time tumor tracking to breathing motion variations

NASA Astrophysics Data System (ADS)

Seregni, M.; Cerveri, P.; Riboldi, M.; Pella, A.; Baroni, G.

2012-11-01

In radiotherapy, organ motion mitigation by means of dynamic tumor tracking requires continuous information about the internal tumor position, which can be estimated relying on external/internal correlation models as a function of external surface surrogates. In this work, we propose a validation of a time-independent artificial neural networks-based tumor tracking method in the presence of changes in the breathing pattern, evaluating the performance on two datasets. First, simulated breathing motion traces were specifically generated to include gradually increasing respiratory irregularities. Then, seven publically available human liver motion traces were analyzed for the assessment of tracking accuracy, whose sensitivity with respect to the structural parameters of the model was also investigated. Results on simulated data showed that the proposed method was not affected by hysteretic target trajectories and it was able to cope with different respiratory irregularities, such as baseline drift and internal/external phase shift. The analysis of the liver motion traces reported an average RMS error equal to 1.10 mm, with five out of seven cases below 1 mm. In conclusion, this validation study proved that the proposed method is able to deal with respiratory irregularities both in controlled and real conditions.

Quantitative evaluation of pancreatic tumor fibrosis using shear wave elastography.

PubMed

Kuwahara, Takamichi; Hirooka, Yoshiki; Kawashima, Hiroki; Ohno, Eizaburo; Sugimoto, Hiroyuki; Hayashi, Daijuro; Morishima, Tomomasa; Kawai, Manabu; Suhara, Hiroki; Takeyama, Tomoaki; Yamamura, Takeshi; Funasaka, Kohei; Nakamura, Masanao; Miyahara, Ryoji; Watanabe, Osamu; Ishigami, Masatoshi; Shimoyama, Yoshie; Nakamura, Shigeo; Hashimoto, Senju; Goto, Hidemi

There is no established non-invasive method for diagnosis of pancreatic fibrosis. Shear wave elastography (SW-EG) may be a candidate for this purpose. The aims of this study were to assess the reproducibility of SW-EG in the normal imaging pancreas (Phase 1) and to evaluate the diagnostic performance of SW-EG for pancreatic fibrosis classified histologically (Phase 2). Phase 1: This included 127 cases that underwent SW-EG of the normal imaging pancreas. SW-EG was measured at least five times in the pancreatic parenchyma and the median of repeated measurements was defined as the pancreatic elastic modulus (PEM). Phase 2: This included 53 cases that underwent SW-EG of the pancreatic parenchyma preoperatively and in which pancreas parenchyma were evaluated histologically. Histological fibrosis was graded in 4 stages: normal, mild, moderate, and severe. Phase 1: Median PEM in the head, body, and tail of the pancreas were 3.23, 3.17, and 2.91 kPa, respectively, with no significant difference among regions (P = 0.554). The intraclass correlation coefficient showed good reproducibility (ρ = 0.71) after 5 measurements. Phase 2: There was a significant positive correlation between PEM and the histological pancreatic fibrosis stage (r s  = 0.63, P < 0.001). Areas under the receiver operating characteristic curve for the accuracy of SW-EG for diagnosis of pancreatic fibrosis were 0.85 (≥mild), 0.84 (≥moderate), and 0.87 (severe). SW-EG can be used to determine the stage of pancreatic fibrosis non-invasively with high accuracy and reproducibility. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C 82(OH) 22 and its implication for de novo design of nanomedicine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, S. -g.; Zhou, G.; Yang, P.

2012-09-18

Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth-leading cause of cancer-related death in North America. Matrix metalloproteinases (MMPs) have long been targeted as a potential anticancer therapy because of their seminal role in angiogenesis and extracellular matrix (ECM) degradation of tumor survival and invasion. However, the inhibition specificity to MMPs and the molecular-level understanding of the inhibition mechanism remain largely unresolved. Here, we found that endohedral metallofullerenol Gd@C 82(OH) 22 can successfully inhibit the neoplastic activity with experiments at animal, tissue, and cellular levels. Gd@C 82(OH) 22 effectively blocks tumor growth in human pancreatic cancermore » xenografts in a nude mouse model. Enzyme activity assays also show Gd@C 82(OH) 22 not only suppresses the expression of MMPs but also significantly reduces their activities. We then applied large-scale molecular-dynamics simulations to illustrate the molecular mechanism by studying the Gd@C 82(OH) 22–MMP-9 interactions in atomic detail. Our data demonstrated that Gd@C 82(OH) 22 inhibits MMP-9 mainly via an exocite interaction, whereas the well-known zinc catalytic site only plays a minimal role. Steered by nonspecific electrostatic, hydrophobic, and specific hydrogen-bonding interactions, Gd@C 82(OH) 22 exhibits specific binding modes near the ligand-specificity loop S1', thereby inhibiting MMP-9 activity. Both the suppression of MMP expression and specific binding mode make Gd@C 82(OH) 22 a potentially more effective nanomedicine for pancreatic cancer than traditional medicines, which usually target the proteolytic sites directly but fail in selective inhibition. Finally, our findings provide insights for de novo design of nanomedicines for fatal diseases such as pancreatic cancer.« less

[Autoimmune pancreatitis. Evidence based management guidelines of the Hungarian Pancreatic Study Group].

PubMed

Dubravcsik, Zsolt; Farkas, Gyula; Hegyi, Péter; Hritz, István; Kelemen, Dezső; Lásztity, Natália; Morvay, Zita; Oláh, Attila; Pap, Ákos; Párniczky, Andrea; Sahin-Tóth, Miklós; Szentkereszti, Zsolt; Szmola, Richárd; Takács, Tamás; Tiszlavicz, László; Szücs, Ákos; Czakó, László

2015-02-22

Autoimmune pancreatitis is a rare disease which can even mimic pancreatic tumor, however, unlike the latter, it requires not surgical but conservative management. Correct diagnosis and differential diagnosis of autoimmune pancreatitis and treatment of these patients requires up-to-date and evidence based management guidelines. The Hungarian Pancreatic Study Group proposed to prepare an evidence based guideline based on the available international guidelines and evidences. The preparatory and consultation task force appointed by the Hungarian Pancreatic Study Group translated and complemented and/or modified the international guidelines if it was necessary. 29 relevant clinical questions in 4 topics were defined (Basics; Diagnosis; Differential diagnostics; Therapy). Evidence was classified according to the UpToDate(®) grading system. The draft of the guidelines was presented and discussed at the consensus meeting on September 12, 2014. All clinial questions were accepted with almost total (more than 95%) agreement. The present guideline is the first evidence based autoimmune pancreatitis guideline in Hungary. The guideline may provide very important and helpful data for tuition of autoimmune pancreatitis, for everyday practice and for establishing proper finance. Therefore, the authors believe that these guidelines will widely become a basic reference in Hungary.

Pancreatic sarcoidosis discovered during Whipple procedure.

PubMed

Cook, Jonathan; Spees, Tanner; Telefus, Phillip; Ranaudo, Jeffrey M; Carryl, Stephen; Xiao, Philip

2013-04-04

Pancreatic sarcoidosis is a rare variant of systemic sarcoidosis, with cases described in literature as recently as January 2010. We present here a case of pancreatic involvement with non-caseating granulomas discovered on laparotomy in a patient with a preoperative diagnosis of pancreatic carcinoma. Computer tomography scan without contrast revealed a well-marginated smooth-shaped tumor in the head of the pancreas morphologically consistent with malignancy. During Whipple procedure, the mass was found to be a large lymph node that contained numerous non-caseating granulomas. Radiologically and clinically, non-caseating granulomas of the pancreas are often misdiagnosed as malignant tumor. Special attention given to this differential diagnosis by surgeons, pathologists and clinicians can avoid misdiagnosis and unnecessary treatment. Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author 2013.

The effectiveness of a pneumatic compression belt in reducing respiratory motion of abdominal tumors in patients undergoing stereotactic body radiotherapy.

PubMed

Lovelock, D Michael; Zatcky, Joan; Goodman, Karyn; Yamada, Yoshiya

2014-06-01

Abdominal compression using a pneumatic abdominal compression belt developed in-house has been used to reduce respiratory motion of patients undergoing hypo-fractionated or single fraction stereotactic radio-ablative therapy for abdominal cancers. The clinical objective of belt usage was to reduce the cranial-caudal (CC) respiratory motion of the tumor to 5 mm or less during both CT simulation and treatment. A retrospective analysis was done to determine the effectiveness of the device and associated clinical procedures to reduce the CC respiratory motion of the tumor. 42 patients treated for tumors in the liver (30), adrenal glands (6), pancreas (3) and lymph nodes (3) using high dose hypofractionated radiotherapy between 2004 and the present were eligible for analysis. All patients had 2-3 radiopaque fiducial markers implanted near the tumor prior to simulation, or had clips from prior surgery. Integral to the belt is an inflatable air bladder that is positioned over the abdomen. The pneumatic pressure was set to a level in consultation with the patient. The CC motion was measured fluoroscopically with and without pneumatic pressure. Pneumatic pressure was used at all treatments to reduce to CC motion to that achieved at simulation. The mean CC motion with the belt in place, but no additional air pressure was 11.4 mm with a range of 5-20 mm. With the pressure applied, the mean CC motion was reduced to 4.4 mm with a range of 1-8 mm (P-value < 0.001). The clinical objective of reducing the CC motion of the tumor to a maximum excursion of 5 mm or less was achieved in 93% of cases. The use of a pneumatic compression belt and associated clinical procedures was found to result in a significant and frequently substantial reduction in the CC motion of the tumor.

SU-E-J-253: Evaluation of 4DCT Images with Correlation of RPM Signals to Tumor Motion for Respiratory-Gated Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, TK; Ewald, A; Schultz, T

2014-06-01

Purpose: The amplitudes of lung tumor target motion and RPM signals are different from each other. Also, RPM system does not have in-depth RPM signal analysis tool. We have developed an algorithm that analyzes RPM signals for its stability as well as correlativity to the tumor motion. Methods: We used a Philips Big Bore CT scanner with a Varian Real-Time Position Management™ (RPM) system attached. 4DCT images were reviewed and tumor motion amplitudes of full breathing in superior-inferior, anterior-posterior, and left-right directions were measured. RPM signals were analyzed with the algorithm developed with Matlab. Average signal period, amplitude and statisticalmore » stability of the full breathing pattern as well as the pattern around full expiration were calculated. RPM signal amplitudes were normalized to measured tumor motion amplitudes so that selected gating phases (30%–70% or 40%–60%) allow tumor motion under 5.0mm. Results: Twelve patient cases were analyzed in this study with GTV sizes ranged from 1.0cm to 3.0cm diameter. The periods and amplitudes of RPM signal ranged from 3.1seconds to 6.5seconds and from 0.2cm to 1.7cm, respectively. RPM signals were most stable at full expiration. The standard deviation of the RPM signal peaks at full expiration was <0.11cm, and that of gated amplitudes was <0.25cm. Tumor motion amplitudes were primary in superior-inferior direction and minor (<=0.2cm) in other directions on all analyzed cases, ranged from 0.2cm to 2.5cm. The amplitudes increases with the tumor located toward the diaphragm. The gated phases were selected so that the average gated tumor motion amplitude as well as that plus deviation became under 0.5cm in superior-inferior direction. Conclusion: We were able to determine the respiratory-gated phases in RPM signals employing measured tumor motion amplitudes as well as developed RPM signal analyzer through correlation process. The RPM signal amplitudes do not represent tumor motion because of

New insights into pancreatic cancer biology.

PubMed

Hidalgo, M

2012-09-01

Pancreatic cancer remains a devastating disease. Over the last few years, there have been important advances in the molecular and biological understanding of pancreatic cancer. This included understanding of the genomic complexity of the disease, the role of pancreatic cancer stem cells, the relevance of the tumor microenvironment, and the unique metabolic adaptation of pancreas cancer cells to obtain nutrients under hypoxic environment. In this paper, we review the most salient developments in these few areas.

A tissue-engineered subcutaneous pancreatic cancer model for antitumor drug evaluation.

PubMed

He, Qingyi; Wang, Xiaohui; Zhang, Xing; Han, Huifang; Han, Baosan; Xu, Jianzhong; Tang, Kanglai; Fu, Zhiren; Yin, Hao

2013-01-01

The traditional xenograft subcutaneous pancreatic cancer model is notorious for its low incidence of tumor formation, inconsistent results for the chemotherapeutic effects of drug molecules of interest, and a poor predictive capability for the clinical efficacy of novel drugs. These drawbacks are attributed to a variety of factors, including inoculation of heterogeneous tumor cells from patients with different pathological histories, and use of poorly defined Matrigel(®). In this study, we aimed to tissue-engineer a pancreatic cancer model that could readily cultivate a pancreatic tumor derived from highly homogenous CD24(+)CD44(+) pancreatic cancer stem cells delivered by a well defined electrospun scaffold of poly(glycolide-co-trimethylene carbonate) and gelatin. The scaffold supported in vitro tumorigenesis from CD24(+)CD44(+) cancer stem cells for up to 7 days without inducing apoptosis. Moreover, CD24(+)CD44(+) cancer stem cells delivered by the scaffold grew into a native-like mature pancreatic tumor within 8 weeks in vivo and exhibited accelerated tumorigenesis as well as a higher incidence of tumor formation than the traditional model. In the scaffold model, we discovered that oxaliplatin-gemcitabine (OXA-GEM), a chemotherapeutic regimen, induced tumor regression whereas gemcitabine alone only capped tumor growth. The mechanistic study attributed the superior antitumorigenic performance of OXA-GEM to its ability to induce apoptosis of CD24(+)CD44(+) cancer stem cells. Compared with the traditional model, the scaffold model demonstrated a higher incidence of tumor formation and accelerated tumor growth. Use of a tiny population of highly homogenous CD24(+)CD44(+) cancer stem cells delivered by a well defined scaffold greatly reduces the variability associated with the traditional model, which uses a heterogeneous tumor cell population and poorly defined Matrigel. The scaffold model is a robust platform for investigating the antitumorigenesis mechanism of

Compensating for Tumor Motion by a 6-Degree-of-Freedom Treatment Couch: Is Patient Tolerance an Issue?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sweeney, Reinhart A.; Arnold, Winfried; Steixner, Eva

2009-05-01

Purpose: To determine whether patients could tolerate the motion of a robotic couch that compensates for breathing-induced tumor motion. Methods and Materials: A total of 10 healthy subjects and 23 radio-oncology patients underwent simulated extracranial stereotactic radiotherapy (two 30-min sessions) on a robotic couch programmed to follow a fictitious tumor trajectory of 20x5x5 mm (cranio-caudal, left-right, and anterior-posterior directions, respectively) while rotating 2 deg. around a cranio-caudal axis at a frequency of 5 seconds per loop. Results: No session had to be interrupted and no nausea was induced. However, one patient refused the second session due to general deterioration andmore » not all patients could keep their arms elevated for the entire session. Conclusions: Our findings showed that most patients tolerated compensatory couch motion and that motion sickness should not pose a problem in the investigation of this tumor-tracking method.« less

Hormone profiling, WHO 2010 grading, and AJCC/UICC staging in pancreatic neuroendocrine tumor behavior

PubMed Central

Morin, Emilie; Cheng, Sonia; Mete, Ozgur; Serra, Stefano; Araujo, Paula B; Temple, Sara; Cleary, Sean; Gallinger, Steven; Greig, Paul D; McGilvray, Ian; Wei, Alice; Asa, Sylvia L; Ezzat, Shereen

2013-01-01

Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic neoplasms, exhibiting a complex spectrum of clinical behaviors. To examine the clinico-pathological characteristics associated with long-term prognosis we reviewed 119 patients with pNETs treated in a tertiary referral center using the WHO 2010 grading and the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging systems, with a median follow-up of 38 months. Tumor size, immunohistochemistry (IHC) profiling and patient characteristics-determining stage were analyzed. Primary clinical outcomes were disease progression or death. The mean age at presentation was 52 years; 55% were female patients, 11% were associated with MEN1 (multiple endocrine neoplasia 1) or VHL (Von Hippel–Lindau); mean tumor diameter was 3.3 cm (standard deviation, SD) (2.92). The clinical presentation was incidental in 39% with endocrine hypersecretion syndromes in only 24% of cases. Nevertheless, endocrine hormone tissue immunoreactivity was identified in 67 (56.3%) cases. According to WHO 2010 grading, 50 (42%), 38 (31.9%), and 3 (2.5%) of tumors were low grade (G1), intermediate grade (G2), and high grade (G3), respectively. Disease progression occurred more frequently in higher WHO grades (G1: 6%, G2: 10.5%, G3: 67%, P = 0.026) and in more advanced AJCC stages (I: 2%, IV: 63%, P = 0.033). Shorter progression free survival (PFS) was noted in higher grades (G3 vs. G2; 21 vs. 144 months; P = 0.015) and in more advanced AJCC stages (stage I: 218 months, IV: 24 months, P < 0.001). Liver involvement (20 vs. 173 months, P < 0.001) or histologically positive lymph nodes (33 vs. 208 months, P < 0.001) were independently associated with shorter PFS. Conversely, tissue endocrine hormone immunoreactivity, independent of circulating levels was significantly associated with less aggressive disease. Age, gender, number of primary tumors, and heredity were not

Pancreatic cancer stromal biology and therapy

PubMed Central

Xie, Dacheng; Xie, Keping

2015-01-01

Pancreatic cancer is one of the most lethal malignancies. Significant progresses have been made in understanding of pancreatic cancer pathogenesis, including appreciation of precursor lesions or premalignant pancreatic intraepithelial neoplasia (PanINs), description of sequential transformation from normal pancreatic tissue to invasive pancreatic cancer and identification of major genetic and epigenetic events and the biological impact of those events on malignant behavior. However, the currently used therapeutic strategies targeting tumor epithelial cells, which are potent in cell culture and animal models, have not been successful in the clinic. Presumably, therapeutic resistance of pancreatic cancer is at least in part due to its drastic desmoplasis, which is a defining hallmark for and circumstantially contributes to pancreatic cancer development and progression. Improved understanding of the dynamic interaction between cancer cells and the stroma is important to better understanding pancreatic cancer biology and to designing effective intervention strategies. This review focuses on the origination, evolution and disruption of stromal molecular and cellular components in pancreatic cancer, and their biological effects on pancreatic cancer pathogenesis. PMID:26114155

Mid-Ventilation Concept for Mobile Pulmonary Tumors: Internal Tumor Trajectory Versus Selective Reconstruction of Four-Dimensional Computed Tomography Frames Based on External Breathing Motion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guckenberger, Matthias; Wilbert, Juergen; Krieger, Thomas

2009-06-01

Purpose: To evaluate the accuracy of direct reconstruction of mid-ventilation and peak-phase four-dimensional (4D) computed tomography (CT) frames based on the external breathing signal. Methods and Materials: For 11 patients with 15 pulmonary targets, a respiration-correlated CT study (4D CT) was acquired for treatment planning. After retrospective time-based sorting of raw projection data and reconstruction of eight CT frames equally distributed over the breathing cycle, mean tumor position (P{sub mean}), mid-ventilation frame, and breathing motion were evaluated based on the internal tumor trajectory. Analysis of the external breathing signal (pressure sensor around abdomen) with amplitude-based sorting of projections was performedmore » for direct reconstruction of the mid-ventilation frame and frames at peak phases of the breathing cycle. Results: On the basis of the eight 4D CT frames equally spaced in time, tumor motion was largest in the craniocaudal direction, with 12 {+-} 7 mm on average. Tumor motion between the two frames reconstructed at peak phases was not different in the craniocaudal and anterior-posterior directions but was systematically smaller in the left-right direction by 1 mm on average. The 3-dimensional distance between P{sub mean} and the tumor position in the mid-ventilation frame based on the internal tumor trajectory was 1.2 {+-} 1 mm. Reconstruction of the mid-ventilation frame at the mean amplitude position of the external breathing signal resulted in tumor positions 2.0 {+-} 1.1 mm distant from P{sub mean}. Breathing-induced motion artifacts in mid-ventilation frames caused negligible changes in tumor volume and shape. Conclusions: Direct reconstruction of the mid-ventilation frame and frames at peak phases based on the external breathing signal was reliable. This makes the reconstruction of only three 4D CT frames sufficient for application of the mid-ventilation technique in clinical practice.« less

Pancreatic tissue assessment using fluorescence and reflectance spectroscopy

NASA Astrophysics Data System (ADS)

Chandra, Malavika; Heidt, David; Simeone, Diane; McKenna, Barbara; Scheiman, James; Mycek, Mary-Ann

2007-07-01

The ability of multi-modal optical spectroscopy to detect signals from pancreatic tissue was demonstrated by studying human pancreatic cancer xenografts in mice and freshly excised human pancreatic tumor tissue. Measured optical spectra and fluorescence decays were correlated with tissue morphological and biochemical properties. The measured spectral features and decay times correlated well with expected pathological differences in normal, pancreatitis and adenocarcinoma tissue states. The observed differences between the fluorescence and reflectance properties of normal, pancreatitis and adenocarcinoma tissue indicate a possible application of multi-modal optical spectroscopy to differentiating between the three tissue classifications.

[Pancreatic ultrasonography].

PubMed

Fernández-Rodríguez, T; Segura-Grau, A; Rodríguez-Lorenzo, A; Segura-Cabral, J M

2015-04-01

Despite the recent technological advances in imaging, abdominal ultrasonography continues to be the first diagnostic test indicated in patients with a suspicion of pancreatic disease, due to its safety, accessibility and low cost. It is an essential technique in the study of inflammatory processes, since it not only assesses changes in pancreatic parenchyma, but also gives an indication of the origin (bile or alcoholic). It is also essential in the detection and tracing of possible complications as well as being used as a guide in diagnostic and therapeutic punctures. It is also the first technique used in the study of pancreatic tumors, detecting them with a sensitivity of around 70% and a specificity of 90%. Copyright © 2014 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

Extended versus peripancreatic lymph node dissection for the treatment of left-sided pancreatic cancer

PubMed Central

Lee, Huisong; Choi, Seong Ho; Choi, Dong Wook

2017-01-01

Purpose The pathways of lymphatic metastases differ according to the tumor location in pancreatic cancer patients. However, it is unclear whether extended lymph node dissection (LND) is essential for all left-sided pancreatic cancer. The aim of this study is to evaluate the survival outcomes according to the extent of LND and tumor location in patients with left-sided pancreatic cancer. Methods January 2005 to December 2013, we retrospectively identified 107 patients who underwent curative intent surgery for left-sided pancreatic cancer. The left-sided pancreatic cancer was defined as a tumor located in pancreatic body or tail. The extent of LND was divided into 2 groups: extended LND and peripancreatic LND. The extended LND group included celiac and superior mesenteric LNs. Results We included 107 patients with left-sided pancreatic cancer; 59 patients with pancreatic body cancer and 48 patients with pancreatic tail cancer. The median follow-up period was 17 months (range, 3–110 months). Fifty patients with pancreatic body cancer and 30 patients with pancreatic tail cancer underwent extended LND. In patients with pancreatic body cancer, extended LND was associated with improved disease-free survival (DFS) (P = 0.010) and overall survival (P = 0.014). However, extended LND was not associated with DFS in patients with pancreatic tail cancer. Conclusion Extended LND could improve survival in patients with pancreatic body cancer. However, extended LND had no survival benefit for the treatment of pancreatic tail cancer. PMID:28580345

Extended versus peripancreatic lymph node dissection for the treatment of left-sided pancreatic cancer.

PubMed

Lee, Huisong; Heo, Jin Seok; Choi, Seong Ho; Choi, Dong Wook

2017-06-01

The pathways of lymphatic metastases differ according to the tumor location in pancreatic cancer patients. However, it is unclear whether extended lymph node dissection (LND) is essential for all left-sided pancreatic cancer. The aim of this study is to evaluate the survival outcomes according to the extent of LND and tumor location in patients with left-sided pancreatic cancer. January 2005 to December 2013, we retrospectively identified 107 patients who underwent curative intent surgery for left-sided pancreatic cancer. The left-sided pancreatic cancer was defined as a tumor located in pancreatic body or tail. The extent of LND was divided into 2 groups: extended LND and peripancreatic LND. The extended LND group included celiac and superior mesenteric LNs. We included 107 patients with left-sided pancreatic cancer; 59 patients with pancreatic body cancer and 48 patients with pancreatic tail cancer. The median follow-up period was 17 months (range, 3-110 months). Fifty patients with pancreatic body cancer and 30 patients with pancreatic tail cancer underwent extended LND. In patients with pancreatic body cancer, extended LND was associated with improved disease-free survival (DFS) (P = 0.010) and overall survival (P = 0.014). However, extended LND was not associated with DFS in patients with pancreatic tail cancer. Extended LND could improve survival in patients with pancreatic body cancer. However, extended LND had no survival benefit for the treatment of pancreatic tail cancer.

Palliative Care in Improving Quality of Life and Symptoms in Patients With Stage III-IV Pancreatic or Ovarian Cancer

ClinicalTrials.gov

2014-12-18

Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer

Targeting EGF-receptor(s) - STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer

PubMed Central

Seshacharyulu, Parthasarathy; Ponnusamy, Moorthy P.; Rachagani, Satyanarayana; Lakshmanan, Imayavaramban; Haridas, Dhanya; Yan, Ying; Ganti, Apar K.; Batra, Surinder K.

2015-01-01

Transmembrane proteins MUC4, EGFR and HER2 are shown to be critical in invasion and metastasis of pancreatic cancer. Besides, we and others have demonstrated de novo expression of MUC4 in ~70-90% of pancreatic cancer patients and its stabilizing effects on HER2 downstream signaling in pancreatic cancer. Here, we found that use of canertinib or afatinib resulted in reduction of MUC4 and abrogation of in vitro and in vivo oncogenic functions of MUC4 in pancreatic cancer cells. Notably, silencing of EGFR family member in pancreatic cancer cells decreased MUC4 expression through reduced phospho-STAT1. Furthermore, canertinib and afatinib treatment also inhibited proliferation, migration and survival of pancreatic cancer cells by attenuation of signaling events including pERK1/2 (T202/Y204), cyclin D1, cyclin A, pFAK (Y925) and pAKT (Ser473). Using in vivo bioluminescent imaging, we demonstrated that canertinib treatment significantly reduced tumor burden (P=0.0164) and metastasis to various organs. Further, reduced expression of MUC4 and EGFR family members were confirmed in xenografts. Our results for the first time demonstrated the targeting of EGFR family members along with MUC4 by using pan-EGFR inhibitors. In conclusion, our studies will enhance the translational acquaintance of pan-EGFR inhibitors for combinational therapies to combat against lethal pancreatic cancer. PMID:25686822

Targeting EGF-receptor(s) - STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer.

PubMed

Seshacharyulu, Parthasarathy; Ponnusamy, Moorthy P; Rachagani, Satyanarayana; Lakshmanan, Imayavaramban; Haridas, Dhanya; Yan, Ying; Ganti, Apar K; Batra, Surinder K

2015-03-10

Transmembrane proteins MUC4, EGFR and HER2 are shown to be critical in invasion and metastasis of pancreatic cancer. Besides, we and others have demonstrated de novo expression of MUC4 in ~70-90% of pancreatic cancer patients and its stabilizing effects on HER2 downstream signaling in pancreatic cancer. Here, we found that use of canertinib or afatinib resulted in reduction of MUC4 and abrogation of in vitro and in vivo oncogenic functions of MUC4 in pancreatic cancer cells. Notably, silencing of EGFR family member in pancreatic cancer cells decreased MUC4 expression through reduced phospho-STAT1. Furthermore, canertinib and afatinib treatment also inhibited proliferation, migration and survival of pancreatic cancer cells by attenuation of signaling events including pERK1/2 (T202/Y204), cyclin D1, cyclin A, pFAK (Y925) and pAKT (Ser473). Using in vivo bioluminescent imaging, we demonstrated that canertinib treatment significantly reduced tumor burden (P=0.0164) and metastasis to various organs. Further, reduced expression of MUC4 and EGFR family members were confirmed in xenografts. Our results for the first time demonstrated the targeting of EGFR family members along with MUC4 by using pan-EGFR inhibitors. In conclusion, our studies will enhance the translational acquaintance of pan-EGFR inhibitors for combinational therapies to combat against lethal pancreatic cancer.

Homozygous KSR1 deletion attenuates morbidity but does not prevent tumor development in a mouse model of RAS-driven pancreatic cancer

PubMed Central

Germino, Elizabeth A.; Miller, Joseph P.; Diehl, Lauri; Durinck, Steffen; Modrusan, Zora; Miner, Jeffrey H.

2018-01-01

Given the frequency with which MAP kinase signaling is dysregulated in cancer, much effort has been focused on inhibiting RAS signaling for therapeutic benefit. KSR1, a pseudokinase that interacts with RAF, is a potential target; it was originally cloned in screens for suppressors of constitutively active RAS, and its deletion prevents RAS-mediated transformation of mouse embryonic fibroblasts. In this work, we used a genetically engineered mouse model of pancreatic cancer to assess whether KSR1 deletion would influence tumor development in the setting of oncogenic RAS. We found that Ksr1-/- mice on this background had a modest but significant improvement in all-cause morbidity compared to Ksr1+/+ and Ksr1+/- cohorts. Ksr1-/- mice, however, still developed tumors, and precursor pancreatic intraepithelial neoplastic (PanIN) lesions were detected within a similar timeframe compared to Ksr1+/+ mice. No significant differences in pERK expression or in proliferation were noted. RNA sequencing also did not reveal any unique genetic signature in Ksr1-/- tumors. Further studies will be needed to determine whether and in what settings KSR inhibition may be clinically useful. PMID:29596465

Infracolic Approach to the Superior Mesenteric Vessels for a Large Pancreatic Tumor with Right Colon Invasion - A Case Report and Literature Review.

PubMed

Bacalbasa, Nicolae; Balescu, Irina

2017-05-01

Pancreatic cancer remains one of the most aggressive malignancies and is frequently diagnosed in advanced stages when local invasion is already present. In such cases, curative resection is often not possible; however, in certain cases, local invasion will not preclude radical surgery. We present the case of a 63-year-old patient who was diagnosed with a large pancreatic tumor with right colonic invasion in whom a pancreatoduodenectomy en bloc with right colectomy was successfully performed. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Collagen triple helix repeat containing-1 promotes pancreatic cancer progression by regulating migration and adhesion of tumor cells.

PubMed

Park, Eun Hye; Kim, Seokho; Jo, Ji Yoon; Kim, Su Jin; Hwang, Yeonsil; Kim, Jin-Man; Song, Si Young; Lee, Dong-Ki; Koh, Sang Seok

2013-03-01

Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein involved in vascular remodeling, bone formation and developmental morphogenesis. CTHRC1 has recently been shown to be expressed in human cancers such as breast cancer and melanoma. In this study, we show that CTHRC1 is highly expressed in human pancreatic cancer tissues and plays a role in the progression and metastasis of the disease. CTHRC1 promoted primary tumor growth and metastatic spread of cancer cells to distant organs in orthotopic xenograft tumor mouse models. Overexpression of CTHRC1 in cancer cells resulted in increased motility and adhesiveness, whereas these cellular activities were diminished by down-regulation of the protein. CTHRC1 activated several key signaling molecules, including Src, focal adhesion kinase, paxillin, mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase and Rac1. Treatment with chemical inhibitors of Src, MEK or Rac1 and expression of dominant-negative Rac1 attenuated CTHRC1-induced cell migration and adhesion. Collectively, our results suggest that CTHRC1 has a role in pancreatic cancer progression and metastasis by regulating migration and adhesion activities of cancer cells.

Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

PubMed Central

Ochi, Atsuo; Graffeo, Christopher S.; Zambirinis, Constantinos P.; Rehman, Adeel; Hackman, Michael; Fallon, Nina; Barilla, Rocky M.; Henning, Justin R.; Jamal, Mohsin; Rao, Raghavendra; Greco, Stephanie; Deutsch, Michael; Medina-Zea, Marco V.; Saeed, Usama Bin; Ego-Osuala, Melvin O.; Hajdu, Cristina; Miller, George

2012-01-01

Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and murine pancreatic cancer led us to postulate that carcinogenesis is dependent on TLR7 signaling. In a mouse model of pancreatic cancer, TLR7 ligation vigorously accelerated tumor progression and induced loss of expression of PTEN, p16, and cyclin D1 and upregulation of p21, p27, p53, c-Myc, SHPTP1, TGF-β, PPARγ, and cyclin B1. Furthermore, TLR7 ligation induced STAT3 activation and interfaced with Notch as well as canonical NF-κB and MAP kinase pathways, but downregulated expression of Notch target genes. Moreover, blockade of TLR7 protected against carcinogenesis. Since pancreatic tumorigenesis requires stromal expansion, we proposed that TLR7 ligation modulates pancreatic cancer by driving stromal inflammation. Accordingly, we found that mice lacking TLR7 exclusively within their inflammatory cells were protected from neoplasia. These data suggest that targeting TLR7 holds promise for treatment of human pancreatic cancer. PMID:23023703

Pathogenic mechanisms of pancreatitis

PubMed Central

Manohar, Murli; Verma, Alok Kumar; Venkateshaiah, Sathisha Upparahalli; Sanders, Nathan L; Mishra, Anil

2017-01-01

Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for

Changing the course of pancreatic cancer--Focus on recent translational advances.

PubMed

Javle, Milind; Golan, Talia; Maitra, Anirban

2016-03-01

In the past decade, insightful preclinical research has led to important breakthroughs in our understanding of pancreatic cancer. Even though the vast majority of pancreatic cancers are KRAS mutated, not all pancreatic cancer tumors are "KRAS equal"; there seems to be varying dependencies on the KRAS pathway. While KRAS-targeting therapies have been disappointing in the clinic, 'synthetic lethal' approaches hold promise in this setting. The pancreatic cancer stromal microenvironment appears to have contradictory roles. While there is evidence to suggest that stromal barrier prevents drug delivery, in other circumstances, stroma can play a protective role and its disruption enhances tumor dissemination. Clinical trials aimed at manipulating the various stromal components are in progress. BRCA mutation-related pancreatic tumors illustrate a unique subtype with enhanced susceptibility to DNA damaging agents and PARP-inhibition. DNA repair defects in cancer extend beyond germ line BRCA mutation and may extend the indications for DNA repair-targeting agents. Immune strategies are an area of active investigation in pancreatic cancer. Although the initial trials of single-agent checkpoint inhibitors have been negative, combinational approaches using immune-modifying agents and vaccines appear promising and goal is to identify an 'immune-therapy responsive' profile in pancreatic cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Herpes simplex virus amplicon delivery of a hypoxia-inducible soluble vascular endothelial growth factor receptor (sFlk-1) inhibits angiogenesis and tumor growth in pancreatic adenocarcinoma.

PubMed

Reinblatt, Maura; Pin, Richard H; Bowers, William J; Federoff, Howard J; Fong, Yuman

2005-12-01

Tumor hypoxia induces vascular endothelial growth factor (VEGF) expression, which stimulates angiogenesis and tumor proliferation. The VEGF signaling pathway is inhibited by soluble VEGF receptors (soluble fetal liver kinase 1; sFlk-1), which bind VEGF and block its interaction with endothelial cells. Herpes simplex virus (HSV) amplicons are replication-incompetent viruses used for gene delivery. We attempted to attenuate angiogenesis and inhibit pancreatic tumor growth through HSV amplicon-mediated expression of sFlk-1 under hypoxic control. A multimerized hypoxia-responsive enhancer (10 x HRE) was cloned upstream of the sFlk-1 gene (10 x HRE/sFlk-1). A novel HSV amplicon expressing 10 x HRE/sFlk-1 was genetically engineered (HSV10 x HRE/sFlk-1).Human pancreatic adenocarcinoma cells (AsPC1) were transduced with HSV10 x HRE/sFlk-1 and incubated in normoxia (21% oxygen) or hypoxia (1% oxygen). Capillary inhibition was evaluated by human umbilical vein endothelial cell assay. Western blot assessed sFlk-1 expression. AsPC1 flank tumor xenografts (n = 24) were transduced with HSV10 x HRE/sFlk-1. Media from normoxic AsPC1 transduced with HSV10 x HRE/sFlk-1 yielded a 36% reduction in capillary formation versus controls (P < .05), whereas hypoxic AsPC1 yielded a 76% reduction (P < .005). Western blot of AsPC1 transduced with HSV10 x HRE/sFlk-1 demonstrated greater sFlk-1 expression in hypoxia versus normoxia. AsPC1 flank tumors treated with HSV10 x HRE/sFlk-1 exhibited a 59% reduction in volume versus controls (P < .000001). HSV amplicon delivery of a hypoxia-inducible soluble VEGF receptor significantly reduces new vessel formation and tumor growth. Tumor hypoxia can thus be used to direct antiangiogenic therapy to pancreatic adenocarcinoma.

Effects of emodin on the demethylation of tumor-suppressor genes in pancreatic cancer PANC-1 cells.

PubMed

Zhang, Hao; Chen, Liang; Bu, He-Qi; Yu, Qing-Jiang; Jiang, Dan-Dan; Pan, Feng-Ping; Wang, Yu; Liu, Dian-Lei; Lin, Sheng-Zhang

2015-06-01

Emodin, a natural anthraquinone derivative isolated from Rheum palmatum, has been reported to inhibit the growth of pancreatic cancer cells through different modes of action; yet, the detailed mechanism remains unclear. In the present study, we hypothesized that emodin exerts its antitumor effect by participating in the regulation of the DNA methylation level. Our research showed that emodin inhibited the growth of pancreatic cancer PANC-1 cells in a dose- and time-dependent manner. Dot-blot results showed that 40 µM emodin significantly inhibited genomic 5 mC expression in the PANC-1 cells, and mRNA-Seq showed that different concentrations of emodin could alter the gene expression profile in the PANC-1 cells. BSP confirmed that the methylation levels of P16, RASSF1A and ppENK were decreased, while concomitantly the unmethylated status was increased. RT-PCR and western blotting results confirmed that the low expression or absence of expression of mRNA and protein in the PANC-1 cells was re-expressed following treatment with emodin. In conclusion, our study for the first time suggests that emodin inhibits pancreatic cancer cell growth, which may be related to the demethylation of tumor-suppressor genes. The related mechanism may be through the inhibition of methyltransferase expression.

Double immunohistochemical staining with MUC4/p53 is useful in the distinction of pancreatic adenocarcinoma from chronic pancreatitis: a tissue microarray-based study.

PubMed

Bhardwaj, Atul; Marsh, William L; Nash, Jason W; Barbacioru, Catalin C; Jones, Susie; Frankel, Wendy L

2007-04-01

Immunohistochemical stains have been used for the distinction of pancreatic adenocarcinoma from chronic pancreatitis. To determine if a double stain for MUC/p53 improved specificity and sensitivity for distinction of pancreatic adenocarcinoma from chronic pancreatitis by comparing maspin, mucin 4 (MUC4), p53, Smad4, and the double stain MUC4/p53. Seventy-four pancreatic adenocarcinomas and 19 chronic pancreatitis cases were retrieved from archival files. Tissue cores were arrayed to create a tissue microarray of 2-mm cores. Sections were stained with antibodies against maspin, MUC4, p53, and Smad4. Additionally, a 2-color, double stain for MUC4 and p53 was developed and evaluated. Five percent or greater staining in either of the cores was considered positive. Intensity (0, 1, 2) and extent (%) of tumor cells staining was also determined. The sensitivity for distinction of pancreatic adenocarcinoma from chronic pancreatitis with maspin, MUC4, p53, and Smad4 was 90%, 77%, 60%, and 63%, respectively; the specificity was 67%, 78%, 88%, and 88%, respectively. When MUC4 and p53 were combined in a double stain, and positive staining for either considered a positive result, the sensitivity increased to 96% but specificity was 73%. When immunoreactivity for both antibodies was necessary for a positive result, sensitivity fell to 39% but specificity was 100%. No correlation was found between intensity or extent of staining with any of the individual stains and tumor differentiation. The double immunohistochemical stain for MUC4/p53 can be a useful diagnostic tool in conjunction with the hematoxylin-eosin-stained section for pancreatic adenocarcinoma, particularly when limited tumor is available for multiple stains.

IGRT/ART phantom with programmable independent rib cage and tumor motion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haas, Olivier C. L., E-mail: o.haas@coventry.ac.uk; Mills, John A.; Land, Imke

2014-02-15

Purpose: This paper describes the design and experimental evaluation of the Methods and Advanced Equipment for Simulation and Treatment in Radiation Oncology (MAESTRO) thorax phantom, a new anthropomorphic moving ribcage combined with a 3D tumor positioning system to move target inserts within static lungs. Methods: The new rib cage design is described and its motion is evaluated using Vicon Nexus, a commercial 3D motion tracking system. CT studies at inhale and exhale position are used to study the effect of rib motion and tissue equivalence. Results: The 3D target positioning system and the rib cage have millimetre accuracy. Each axismore » of motion can reproduce given trajectories from files or individually programmed sinusoidal motion in terms of amplitude, period, and phase shift. The maximum rib motion ranges from 7 to 20 mm SI and from 0.3 to 3.7 mm AP with LR motion less than 1 mm. The repeatability between cycles is within 0.16 mm root mean square error. The agreement between CT electron and mass density for skin, ribcage, spine hard and inner bone as well as cartilage is within 3%. Conclusions: The MAESTRO phantom is a useful research tool that produces programmable 3D rib motions which can be synchronized with 3D internal target motion. The easily accessible static lungs enable the use of a wide range of inserts or can be filled with lung tissue equivalent and deformed using the target motion system.« less

Current Knowledge on Pancreatic Cancer

PubMed Central

Iovanna, Juan; Mallmann, Maria Cecilia; Gonçalves, Anthony; Turrini, Olivier; Dagorn, Jean-Charles

2012-01-01

Pancreatic cancer is the fourth leading cause of cancer death with a median survival of 6 months and a dismal 5-year survival rate of 3–5%. The development and progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways. Therefore, the strategies targeting these molecules as well as their downstream signaling could be promising for the prevention and treatment of pancreatic cancer. However, although targeted therapies for pancreatic cancer have yielded encouraging results in vitro and in animal models, these findings have not been translated into improved outcomes in clinical trials. This failure is due to an incomplete understanding of the biology of pancreatic cancer and to the selection of poorly efficient or imperfectly targeted agents. In this review, we will critically present the current knowledge regarding the molecular, biochemical, clinical, and therapeutic aspects of pancreatic cancer. PMID:22655256

In vitro modeling of human pancreatic duct epithelial cell transformation defines gene expression changes induced by K-ras oncogenic activation in pancreatic carcinogenesis.

PubMed

Qian, Jiaying; Niu, Jiangong; Li, Ming; Chiao, Paul J; Tsao, Ming-Sound

2005-06-15

Genetic analysis of pancreatic ductal adenocarcinomas and their putative precursor lesions, pancreatic intraepithelial neoplasias (PanIN), has shown a multistep molecular paradigm for duct cell carcinogenesis. Mutational activation or inactivation of the K-ras, p16(INK4A), Smad4, and p53 genes occur at progressive and high frequencies in these lesions. Oncogenic activation of the K-ras gene occurs in >90% of pancreatic ductal carcinoma and is found early in the PanIN-carcinoma sequence, but its functional roles remain poorly understood. We show here that the expression of K-ras(G12V) oncogene in a near diploid HPV16-E6E7 gene immortalized human pancreatic duct epithelial cell line originally derived from normal pancreas induced the formation of carcinoma in 50% of severe combined immunodeficient mice implanted with these cells. A tumor cell line established from one of these tumors formed ductal cancer when implanted orthotopically. These cells also showed increased activation of the mitogen-activated protein kinase, AKT, and nuclear factor-kappaB pathways. Microarray expression profiling studies identified 584 genes whose expression seemed specifically up-regulated by the K-ras oncogene expression. Forty-two of these genes have been reported previously as differentially overexpressed in pancreatic cancer cell lines or primary tumors. Real-time PCR confirmed the overexpression of a large number of these genes. Immunohistochemistry done on tissue microarrays constructed from PanIN and pancreatic cancer samples showed laminin beta3 overexpression starting in high-grade PanINs and occurring in >90% of pancreatic ductal carcinoma. The in vitro modeling of human pancreatic duct epithelial cell transformation may provide mechanistic insights on gene expression changes that occur during multistage pancreatic duct cell carcinogenesis.

Liquid biopsy in pancreatic cancer: the beginning of a new era

PubMed Central

Yadav, Dipesh Kumar; Bai, Xueli; Yadav, Rajesh Kumar; Singh, Alina; Li, Guogang; Ma, Tao; Chen, Wei; Liang, Tingbo

2018-01-01

With dismal survival rate pancreatic cancer remains one of the most aggressive and devastating malignancy. Predominantly, due to the absence of a dependable methodology for early identification and limited therapeutic options for advanced disease. However, it takes over 17 years to develop pancreatic cancer from initiation of mutation to metastatic cancer; therefore, if diagnosed early; it may increase overall survival dramatically, thus, providing a window of opportunity for early detection. Recently, genomic expression analysis defined 4 subtypes of pancreatic cancer based on mutated genes. Hence, we need simple and standard, minimally invasive test that can monitor those altered genes or their associated pathways in time for the success of precision medicine, and liquid biopsy seems to be one answer to all these questions. Again, liquid biopsy has an ability to pair with genomic tests. Additionally, liquid biopsy based development of circulating tumor cells derived xenografts, 3D organoids system, real-time monitoring of genetic mutations by circulating tumor DNA and exosome as the targeted drug delivery vehicle holds lots of potential for the treatment and cure of pancreatic cancer. At present, diagnosis of pancreatic cancer is frantically done on the premise of CA19-9 and radiological features only, which doesn't give a picture of genetic mutations and epigenetic alteration involved. In this manner, the current diagnostic paradigm for pancreatic cancer diagnosis experiences low diagnostic accuracy. This review article discusses the current state of liquid biopsy in pancreatic cancer as diagnostic and therapeutic tools and future perspectives of research in the light of circulating tumor cells, circulating tumor DNA and exosomes.

Stimulation of islet cell proliferation enhances pancreatic ductal carcinogenesis in the hamster model.

PubMed Central

Pour, P. M.; Kazakoff, K.

1996-01-01

Previous studies have shown that some N-nitrosobis (2-oxopropyl)amine (BOP)-induced ductal/ductular pancreatic cancers in the hamster model develop within islets and that streptozotocin (SZ) pretreatment that caused islet degeneration and atrophy inhibits pancreatic cancer induction. Hence, it appears that in this model islets play a significant role in exocrine pancreatic carcinogenesis. To examine whether stimulation of islet cell proliferation (nesidioblastosis) enhances pancreatic exocrine cancer development, we tested the effect of the pancreatic carcinogen BOP in hamsters after induction of nesidioblastosis by cellophane wrapping. Before wrapping, hamsters were treated with SZ to inhibit pancreatic tumor induction in the unwrapped pancreatic tissues. Control groups with a wrapped pancreas did not receive SZ. Six weeks after SZ treatment, all hamsters were treated with BOP (10 mg/kg body weight) weekly for 10 weeks and the experiment was terminated 38 weeks after the last BOP treatment. Many animals recovered from their diabetes at the time when BOP was injected and many more after BOP treatment. Only nine hamsters remained diabetic until the end of the experiment. Both SZ-treated and control groups developed proliferative and malignant pancreatic ductal-type lesions primarily in the wrapped area (47%) but less frequently in the larger segments of the pancreas, including the splenic lobe (34%), gastric lobe (13%), and duodenal lobe (6%). Only a few lesions developed in the unwrapped pancreatic region of nine diabetic hamsters with atrophic islets, whereas seven of these hamsters had tumors in the wrapped area. Histologically, most tumors appeared to originate from islets, many invasive carcinomas had foci of islets, and some tumor cells showed reactivity with anti-insulin. The results show that, in the BOP hamster model, islets are the site of formation of the major fraction of exocrine pancreatic cancer and that induction of nesidioblastosis enhances

Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia.

PubMed

Badea, Liviu; Herlea, Vlad; Dima, Simona Olimpia; Dumitrascu, Traian; Popescu, Irinel

2008-01-01

The precise details of pancreatic ductal adenocarcinoma (PDAC) pathogenesis are still insufficiently known, requiring the use of high-throughput methods. However, PDAC is especially difficult to study using microarrays due to its strong desmoplastic reaction, which involves a hyperproliferating stroma that effectively "masks" the contribution of the minoritary neoplastic epithelial cells. Thus it is not clear which of the genes that have been found differentially expressed between normal and whole tumor tissues are due to the tumor epithelia and which simply reflect the differences in cellular composition. To address this problem, laser microdissection studies have been performed, but these have to deal with much smaller tissue sample quantities and therefore have significantly higher experimental noise. In this paper we combine our own large sample whole-tissue study with a previously published smaller sample microdissection study by Grützmann et al. to identify the genes that are specifically overexpressed in PDAC tumor epithelia. The overlap of this list of genes with other microarray studies of pancreatic cancer as well as with the published literature is impressive. Moreover, we find a number of genes whose over-expression appears to be inversely correlated with patient survival: keratin 7, laminin gamma 2, stratifin, platelet phosphofructokinase, annexin A2, MAP4K4 and OACT2 (MBOAT2), which are all specifically upregulated in the neoplastic epithelia, rather than the tumor stroma. We improve on other microarray studies of PDAC by putting together the higher statistical power due to a larger number of samples with information about cell-type specific expression and patient survival.

Preventive medicine for von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

PubMed

Krauss, Tobias; Ferrara, Alfonso Massimiliano; Links, Thera P; Wellner, Ulrich; Bancos, Irina; Kvachenyuk, Andrey; Villar Gómez de Las Heras, Karina; Yukina, Marina; Petrov, Roman; Bullivant, Garrett; von Duecker, Laura; Jadhav, Swati S; Ploeckinger, Ursula; Welin, Staffan; Schalin-Jantti, Camilla; Gimm, Oliver; Pfeifer, Marija; Ngeow, Joanne; Hasse-Lazar, Kornelia; Sanso, Gabriela; Qi, Xiao-Ping; Ugurlu, Umit; Diaz, Rene Eduardo; Wohllk, Nelson; Peczkowska, Mariola; Aberle, Jens; Lourenço, Delmar Muniz; Pereira, Maria Adelaide; Fragoso, Maria Candida Barisson Villares; Hoff, Ana O; Almeida, Madson Queiroz; Violante, Alice H D; Quidute, Ana R P; Zhang, Zheiwei; Recasens, Monica; Robles Diaz, Luis; Kunavisarut, Tada; Wannachalee, Taweesak; Sirinvaravong, Sirinart; Jonasch, Eric; Grozinsky-Glasberg, Simona; Fraenkel, Merav; Beltsevich, Dmitry; Egorov, Viacheslav I; Bausch, Dirk; Schott, Matthias; Tiling, Nikolaus; Pennelli, Gianmaria; Zschiedrich, Stefan; Därr, Roland; Ruf, Juri; Denecke, Timm; Link, Karl-Heinrich; Zovato, Stefania; von Dobschuetz, Ernst; Yaremchuk, Svetlana; Amthauer, Holger; Makay, Ozer; Patocs, Attila; Walz, Martin K; Huber, Tobias B; Seufert, Jochen; Hellman, Per; Kim, Raymond H; Kuchinskaya, Ekaterina; Schiavi, Francesca; Malinoc, Angelica; Reisch, Nicole; Jarzab, Barbara; Barontini, Marta; Januszewicz, Andrzej; Shah, Nalini; Young, William; Opocher, Giuseppe; Eng, Charis; Neumann, Hartmut P H; Bausch, Birke

2018-05-10

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2,330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P<0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P=0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cutoff ≥2.8 cm, 44% and 91% for TVDT cutoff of ≤24 months). In 117/273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8cm vs ≥2.8 cm (94% vs 85% by 10 years; P=0.020; 80% vs 50% at 10 years; P=0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Six Degrees-of-Freedom Prostate and Lung Tumor Motion Measurements Using Kilovoltage Intrafraction Monitoring

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Chen-Yu; Tehrani, Joubin Nasehi; Ng, Jin Aun

2015-02-01

Purpose: Tumor positional uncertainty has been identified as a major issue that deteriorates the efficacy of radiation therapy. Tumor rotational movement, which is not well understood, can result in significant geometric and dosimetric inaccuracies. The objective of this study was to measure 6 degrees-of-freedom (6 DoF) prostate and lung tumor motion, focusing on the more novel rotation, using kilovoltage intrafraction monitoring (KIM). Methods and Materials: Continuous kilovoltage (kV) projections of tumors with gold fiducial markers were acquired during radiation therapy for 267 fractions from 10 prostate cancer patients and immediately before or after radiation therapy for 50 fractions from 3more » lung cancer patients. The 6 DoF motion measurements were determined from the individual 3-dimensional (3D) marker positions, after using methods to reject spurious and smooth noisy data, using an iterative closest point algorithm. Results: There were large variations in the magnitude of the tumor rotation among different fractions and patients. Various rotational patterns were observed. The average prostate rotation angles around the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) axes were 1.0 ± 5.0°, 0.6 ± 3.3°, and 0.3 ± 2.0°, respectively. For 35% of the time, the prostate rotated more than 5° about the LR axis, indicating the need for intrafractional adaptation during radiation delivery. For lung patients, the average LR, SI, and AP rotation angles were 0.8 ± 4.2°, −0.8 ± 4.5°, and 1.7 ± 3.1°, respectively. For about 30% of the time, the lung tumors rotated more than 5° around the SI axis. Respiration-induced rotation was detected in 2 of the 3 lung patients. Conclusions: The prostate and lung tumors were found to undergo rotations of more than 5° for about a third of the time. The lung tumor data represent the first 6 DoF tumor motion measured by kV images. The 6 DoF KIM method can enable rotational and

Anti-Hu paraneoplastic brainstem encephalitis caused by a pancreatic neuroendocrine tumor presenting with central hypoventilation.

PubMed

Najjar, Marc; Taylor, Andrew; Agrawal, Surbhi; Fojo, Tito; Merkler, Alexander E; Rosenblum, Marc K; Lennihan, Laura; Kluger, Michael D

2017-06-01

Paraneoplastic neurological syndromes are rare autoimmune manifestations of malignancies associated with specific antibodies. Anti-Hu associated brainstem encephalitis, a well-described syndrome, usually presents subacutely with preferential involvement of the medulla. Anti-Hu antibodies target intraneuronal antigens and are therefore highly correlated with neurological syndromes when present concomitantly with a neoplasm. Reported is a case of anti-Hu brainstem encephalitis associated with a pancreatic neuroendocrine tumor (PNET) presenting with central hypoventilation. This is the first described case of brainstem encephalitis associated with a well-differentiated PNET as well as the first case of Anti-Hu antibodies associated with a PNET. There are no standardized protocols for the treatment of paraneoplastic brainstem encephalitis however, as in the present case, surgical resection and oncological treatment of the tumor is the first line treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Improved Pancreatic Adenocarcinoma Diagnosis in Jaundiced and Non-Jaundiced Pancreatic Adenocarcinoma Patients through the Combination of Routine Clinical Markers Associated to Pancreatic Adenocarcinoma Pathophysiology.

PubMed

Ferri, María José; Saez, Marc; Figueras, Joan; Fort, Esther; Sabat, Miriam; López-Ben, Santiago; de Llorens, Rafael; Aleixandre, Rosa Núria; Peracaula, Rosa

2016-01-01

There is still no reliable biomarker for the diagnosis of pancreatic adenocarcinoma. Carbohydrate antigen 19-9 (CA 19-9) is a tumor marker only recommended for pancreatic adenocarcinoma follow-up. One of the clinical problems lies in distinguishing between this cancer and other benign pancreatic diseases such as chronic pancreatitis. In this study we will assess the value of panels of serum molecules related to pancreatic cancer physiopathology to determine whether alone or in combination could help to discriminate between these two pathologies. CA 19-9, carcinoembryonic antigen (CEA), C-reactive protein, albumin, insulin growth factor-1 (IGF-1) and IGF binding protein-3 were measured using routine clinical analyzers in a cohort of 47 pancreatic adenocarcinoma, 20 chronic pancreatitis and 15 healthy controls. The combination of CA 19-9, IGF-1 and albumin resulted in a combined area under the curve (AUC) of 0.959 with 93.6% sensitivity and 95% specificity, much higher than CA 19-9 alone. An algorithm was defined to classify the patients as chronic pancreatitis or pancreatic cancer with the above specificity and sensitivity. In an independent validation group of 20 pancreatic adenocarcinoma and 13 chronic pancreatitis patients, the combination of the four molecules classified correctly all pancreatic adenocarcinoma and 12 out of 13 chronic pancreatitis patients. Although this panel of markers should be validated in larger cohorts, the high sensitivity and specificity values and the convenience to measure these parameters in clinical laboratories shows great promise for improving pancreatic adenocarcinoma diagnosis.

TLR9 ligation in pancreatic stellate cells promotes tumorigenesis

PubMed Central

Zambirinis, Constantinos P.; Levie, Elliot; Nguy, Susanna; Avanzi, Antonina; Barilla, Rocky; Xu, Yijie; Seifert, Lena; Daley, Donnele; Greco, Stephanie H.; Deutsch, Michael; Jonnadula, Saikiran; Torres-Hernandez, Alejandro; Tippens, Daniel; Pushalkar, Smruti; Eisenthal, Andrew; Saxena, Deepak; Ahn, Jiyoung; Hajdu, Cristina; Engle, Dannielle D.; Tuveson, David

2015-01-01

Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis. PMID:26481685

[Pancreatic cancer. Epidemiology, etiology, diagnosis and therapy].

PubMed

Weber, W; von Essen, C F; Metzger, U; Stalder, G A

1983-03-26

The prognosis of pancreatic adenocarcinoma is still very poor. Research activities have, however, been instituted recently in all fields. Epidemiologic studies indicate etiologic roles of diabetes mellitus, smoking, and meat and coffee consumption. Sonography of the pancreas is at present the best screening method. The significance of computerized tomography, endoscopic retrograde cholangiopancreatography (ERCP), arteriography and tumor markers is discussed. A TNM staging system and prognostic factors are presented. Resection is the treatment of choice for organ-limited pancreatic cancer. The development of new radiation modalities (e.g. pi-mesons) promises improved loco-regional tumor control. The most effective chemotherapy consists of combinations containing 5-fluorouracil, adriamycin and mitomycin-C. Intensive future research in the field of pancreatic cancer is essential if the prognosis of this devastating disease is to be improved.

Mutant KRAS Circulating Tumor DNA Is an Accurate Tool for Pancreatic Cancer Monitoring.

PubMed

Perets, Ruth; Greenberg, Orli; Shentzer, Talia; Semenisty, Valeria; Epelbaum, Ron; Bick, Tova; Sarji, Shada; Ben-Izhak, Ofer; Sabo, Edmond; Hershkovitz, Dov

2018-05-01

Many new pancreatic cancer treatment combinations have been discovered in recent years, yet the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains grim. The advent of new treatments highlights the need for better monitoring tools for treatment response, to allow a timely switch between different therapeutic regimens. Circulating tumor DNA (ctDNA) is a tool for cancer detection and characterization with growing clinical use. However, currently, ctDNA is not used for monitoring treatment response. The high prevalence of KRAS hotspot mutations in PDAC suggests that mutant KRAS can be an efficient ctDNA marker for PDAC monitoring. Seventeen metastatic PDAC patients were recruited and serial plasma samples were collected. CtDNA was extracted from the plasma, and KRAS mutation analysis was performed using next-generation sequencing and correlated with serum CA19-9 levels, imaging, and survival. Plasma KRAS mutations were detected in 5/17 (29.4%) patients. KRAS ctDNA detection was associated with shorter survival (8 vs. 37.5 months). Our results show that, in ctDNA positive patients, ctDNA is at least comparable to CA19-9 as a marker for monitoring treatment response. Furthermore, the rate of ctDNA change was inversely correlated with survival. Our results confirm that mutant KRAS ctDNA detection in metastatic PDAC patients is a poor prognostic marker. Additionally, we were able to show that mutant KRAS ctDNA analysis can be used to monitor treatment response in PDAC patients and that ctDNA dynamics is associated with survival. We suggest that ctDNA analysis in metastatic PDAC patients is a readily available tool for disease monitoring. Avoiding futile chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) patients by monitoring response to treatment is of utmost importance. A novel biomarker for monitoring treatment response in PDAC, using mutant KRAS circulating tumor DNA (ctDNA), is proposed. Results, although limited by small sample numbers

Pancreatoduodenectomy for circumportal pancreas accompanying the retroportal pancreatic duct: a case report and review of the literature.

PubMed

Shonaka, Tatsuya; Inagaki, Mitsuhiro; Akabane, Hiromitsu; Yanagida, Naoyuki; Shomura, Hiroki; Kudo, Takeaki; Orimo, Tatsuya; Oikawa, Futoshi; Aiyama, Takeshi; Yanagawa, Nobuyuki; Oikawa, Kensuke; Nakano, Shiro

2012-10-01

Circumportal pancreas (CP) is an extremely rare pancreatic fusion anomaly which is usually asymptomatic. This report presents the case of a patient with a tumor in the head of a CP and the retroportal accessory pancreatic duct in the pancreatic tissue behind the portal vein. A 53-year-old male was diagnosed with a nonfunctioning neuroendocrine tumor of the pancreas and resection of the tumor was scheduled. The patient was revealed to have CP on preoperative computed tomography and endoscopic retrograde cholangiopancreatography, which showed the pancreatic tissue encircling the portal vein and the retroportal accessory pancreatic duct. The patient safely underwent pylorus-preserving pancreatoduodenectomy reconstructed with pancreaticogastrostomy.